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Gallbladder Wall Thickness as a Non-Invasive Marker for Esophageal Varices: A Systematic Review and Meta-Analysis

Published:September 30, 2022DOI:https://doi.org/10.1016/j.jceh.2022.09.004

      Background

      The early detection of esophageal varices (EV) is important in patients with chronic liver disease (CLD). Non-invasive diagnostic markers are preferred to avoid the cost and potential complications associated with endoscopy. The gallbladder venous blood is drained via small veins which terminate in the portal venous circulation. Therefore, the gallbladder wall thickness (GBWT) can be affected by portal hypertension. We conducted the present study to evaluate the diagnostic and predictive utility of ultrasound GBWT measurement in patients with EV.

      Methods

      We searched PubMed, Scopus, Web of Science and Embase for relevant studies up to March 15, 2022, using the keywords “varix”, “varices”, and “gallbladder” to search the databases by title and abstract. Our meta-analysis was performed using the “meta” package of R software version 4.1.0 and meta-disc for diagnostic test accuracy (DTA).

      Results

      We included 12 studies in our review (N = 1343 participants). The gallbladder thickness was significantly larger in patients with EV compared with the control group (MD = 1.86 mm; 95% CI, 1.36–2.36). The DTA analysis and summary ROC plot showed an AUC of 86% and Q∗ = 0.80. The pooled sensitivity was 73% and the specificity was 86%

      Conclusions

      Our analysis shows that GBWT measurement is a promising predictor of esophageal varices in chronic liver disease patients.

      Keywords

      Abbreviations:

      CI (Confidence interval), DOR (Diagnostic odds ratio), EV (Esophageal varices)
      Esophageal varices (EV) are dilated submucosal veins in the lower esophagus connecting the portal circulation with the systemic circulation.
      • Meseeha M.
      • Attia M.
      Esophageal varices.
      It occurs in patients with chronic liver diseases (CLD) especially those with liver cirrhosis. As the liver becomes fibrotic, interrupting the blood flow increases the pressure in the portal vein, leading to portal hypertension. As a compensatory mechanism, portosystemic collaterals develop. These collaterals, however, cannot tolerate the high portal pressure and become dilated.
      • Cushman J.
      Chapter 44 - portal hypertension and esophageal varices.
      ,
      • Awad J.
      • Wattacheril J.
      Chapter 75B - esophageal varices: acute management of portal hypertension.
      In a former study, EV were found in 71.9% of patients with Child-Pugh class B/C and 42.7% of patients with Child-Pugh class A.
      • Kovalak M.
      • Lake J.
      • Mattek N.
      • Eisen G.
      • Lieberman D.
      • Zaman A.
      Endoscopic screening for varices in cirrhotic patients: data from a national endoscopic database.
      The incidence of EV in patients with cirrhosis at 1 year was 5% and at 3 years was 28%.
      • Merli M.
      • Nicolini G.
      • Angeloni S.
      • et al.
      Incidence and natural history of small esophageal varices in cirrhotic patients.
      Once EV develop, there is an increased risk of variceal bleeding, which is the second most common cause of death in patients with cirrhosis.
      • Gores G.J.
      • Wiesner R.H.
      • Dickson E.R.
      • Zinsmeister A.R.
      • Jorgensen R.A.
      • Langworthy A.
      Prospective evaluation of esophageal varices in primary biliary cirrhosis: development, natural history, and influence on survival.
      ,
      • D'Amico G.
      • Garcia-Tsao G.
      • Pagliaro L.
      Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies.
       The American Association for the Study of Liver Diseases and many studies recommend performing esophagogastroduodenoscopy in all patients newly diagnosed with liver cirrhosis, but this technique is costly and invasive with potential complications.
      • Spiegel B.M.
      • Targownik L.
      • Dulai G.S.
      • Karsan H.A.
      • Gralnek I.M.
      Endoscopic screening for esophageal varices in cirrhosis: is it ever cost effective?.
      • Aoki N.
      • Kajiyama T.
      • Beck J.R.
      • Cone R.W.
      • Soma K.
      • Fukui T.
      Decision analysis of prophylactic treatment for patients with high-risk esophageal varices.
      • Garcia-Tsao G.
      • Sanyal A.J.
      • Grace N.D.
      • Carey W.
      Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis.
      • Richardson E.
      • Arastu S.
      • Halegoua-DeMarzio D.
      PRO: esophagogastroduodenoscopy is the preferred modality to screen for the diagnosis of esophageal and gastric varices when the diagnosis of cirrhosis is made.
      Therefore, several non-invasive parameters like spleen and portal vein diameters were tested in the last decade for early detection of EV; however, these parameters still had a moderate sensitivity and specificity.
      • Manatsathit W.
      • Samant H.
      • Kapur S.
      • et al.
      Accuracy of liver stiffness, spleen stiffness, and LS-spleen diameter to platelet ratio score in detection of esophageal varices: systemic review and meta-analysis.
      The gallbladder venous blood is drained via small veins that terminate in the portal venous circulation. An additional venous part is drained directly into the liver. Therefore, the gallbladder wall thickness (GBWT) can be affected by portal hypertension. Due to impaired drainage of the venous blood, the gallbladder wall becomes thickened.
      • Elkerdawy M.A.
      • Ahmed M.H.
      • Zaghloul M.S.
      • Haseeb M.T.
      • Emara M.H.
      Does gallbladder wall thickness measurement predict esophageal varices in cirrhotic patients with portal hypertension?.
      ,
      • Tsaknakis B.
      • Masri R.
      • Amanzada A.
      • et al.
      Gall bladder wall thickening as non-invasive screening parameter for esophageal varices - a comparative endoscopic - sonographic study.
      Herein, we aimed to perform a systematic review and meta-analysis of diagnostic test accuracy studies to evaluate the predictive ability of GBWT ultrasound measurement for EV in patients with CLD.

      Methods

      The current meta-analysis was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.

      Search Strategy

      A comprehensive systematic search for studies that measured GBWT in patients with EV was performed in PubMed, Scopus, Embase, and web of science using the keywords “varix”, “varices”, “gallbladder”, “gall bladder” to search the databases by title and abstract. No language restrictions were imposed.
      We included studies published up to March 15, 2021. Two researchers (A.E and A.A) independently screened the articles by the titles and abstracts. The full text of potentially relevant articles was reviewed.
      We included articles with the following criteria: studies that included patients with EV due to CLD and reported the GBWT. On the other hand, we excluded animal studies, case reports, studies without sufficient data for GBWT, duplicates, and conference abstracts. We reviewed the reference lists of the included studies for possible relevant studies.

      Extracted Data

      The following data were extracted from each study independently by two authors (A.E and A.A): publication year, study design, age, sex, the mean GBWT measurement in each group, the cut-off values, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) of GBWT in predicting EV. We also extracted the type of ultrasound used in the prediction of EV and cause of the EV as shown in Appendix 1.

      Quality Assessment

      To evaluate the internal validity of the included studies, we used the NIH quality assessment tool for cross-sectional studies and observational cohorts,
      National Heart, Lung, and Blood Institute
      Study Quality Assessment Tools.
      the Newcastle-Ottawa Scale (NOS)
      • Wells G.A.
      • Tugwell P.
      • O’Connell D.
      • et al.
      The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Metaanalyses.
      for appraisal of case-control studies, and the QUADAS-2 tool for diagnostic test accuracy studies.
      • Whiting P.F.
      • Rutjes A.W.
      • Westwood M.E.
      • Mallett S.
      • Deeks J.J.
      • Reitsma J.B.
      the QUADAS-2 Group
      A revised tool for the quality assessment of diagnostic accuracy studies.
      Two reviewers (A.E and A.A) evaluated the included studies independently, and any discrepancy was resolved by discussion.

      Statistical Analysis

      Our meta-analysis was performed using the “meta” package
      • R Core Team RA
      A Language and Environment for Statistical Computing.
      in R software version 4.1.0.
      • Balduzzi S.
      • Rücker G.
      • Schwarzer G.
      How to perform a meta-analysis with R: a practical tutorial.
      We employed the random-effects model to calculate the pooled GBWT in patients with EV and healthy controls. We estimated the statistical heterogeneity across the studies using the inconsistency (I2) and Chi-squared (X2) test. Substantial heterogeneity was considered if I2 > 50%, and the P-value was considered statistically significant if less than 0.05. We estimated the mean difference with a 95% confidence interval for the continuous data. A leave-one-out meta-analysis was conducted to identify the influential studies and to investigate the influence of each study on the overall estimate by excluding one study at a time.
      We also performed the DTA meta-analysis using Meta-Disc software.
      • Zamora J.
      • Abraira V.
      • Muriel A.
      • Khan K.S.
      • Coomarasamy A.
      Meta-DiSc: a software for meta-analysis of test accuracy data.
      We calculated the pooled estimates of sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) and plotted them with 95% confidence interval (CI). We represented the performance of a diagnostic test by plotting the summary receiver operating characteristic (SROC) curve that represents the results for sensitivity and specificity. The curve plots the specificity on the x-axis and the sensitivity on the y-axis. The diagonal stands for the value of sensitivity and specificity of the index test. The better performance of the test, the closer curves to the top-left corner. For the meta-analysis of DTA, we evaluated the heterogeneity using Spearman's correlation coefficient, inconsistency (I
      • Cushman J.
      Chapter 44 - portal hypertension and esophageal varices.
      ), Chi-square test, and Cochran's Q test. We employed the random-effects model of Der Simonian–Laird to estimate the overall effect. If a study reported the GBWT as median (IQR), they were converted to mean ± standard deviation (SD) using the method devised by Hozo et al.
      • Hozo S.P.
      • Djulbegovic B.
      • Hozo I.
      Estimating the mean and variance from the median, range, and the size of a sample.

      Results

      Search Results

      Of 599 articles identified electronically, 230 were duplicates and 24 were eligible after abstract review. A total of 12 studies were included for systematic review, enrolling a total of 1343 participants. Nine studies
      • Elkerdawy M.A.
      • Ahmed M.H.
      • Zaghloul M.S.
      • Haseeb M.T.
      • Emara M.H.
      Does gallbladder wall thickness measurement predict esophageal varices in cirrhotic patients with portal hypertension?.
      ,
      • Tsaknakis B.
      • Masri R.
      • Amanzada A.
      • et al.
      Gall bladder wall thickening as non-invasive screening parameter for esophageal varices - a comparative endoscopic - sonographic study.
      ,
      • Richter J.
      • Monteiro Eda S.
      • Braz R.M.
      • et al.
      Sonographic organometry in Brazilian and Sudanese patients with hepatosplenic schistosomiasis mansoni and its relation to the risk of bleeding from oesophageal varices.
      • Ersoz G.
      • Ozutemiz O.
      • Akarca U.S.
      • Yilmaz M.
      • Karasu Z.
      • Batur Y.
      Gallbladder wall thickening as a sign of esophageal varices in chronic liver disease.
      • Begum S.A.
      • Saibal A.A.
      • Das K.
      • et al.
      Thickening of gallbladder wall in chronic liver disease - a marker for esophageal varices.
      • Petzold G.
      • Tsaknakis B.
      • Bremer S.C.B.
      • et al.
      Evaluation of liver stiffness by 2D-SWE in combination with non-invasive parameters as predictors for esophageal varices in patients with advanced chronic liver disease.
      • Khan M.F.
      • Ullah B.
      • Kadir S.
      • Bajwa M.A.
      Association of gallbladder wall thickness in patients with cirrhosis.
      • Shehata N.M.
      • AbdelAziz A.A.
      • Abd El-Megid M.
      • Hafez Y.M.
      Evaluation of the gallbladder wall thickening as a non-invasive predictor of esophageal varices in cirrhotic patients.
      • Afifi M.
      • Rizk M.
      • Hussein A.
      Gall bladder wall thickness as non-invasive predictor of oesophageal varices in cirrhotic patients.
      were included in our meta-analysis comparing the GBWT between patients with EV and controls. Seven studies
      • Elkerdawy M.A.
      • Ahmed M.H.
      • Zaghloul M.S.
      • Haseeb M.T.
      • Emara M.H.
      Does gallbladder wall thickness measurement predict esophageal varices in cirrhotic patients with portal hypertension?.
      ,
      • Tsaknakis B.
      • Masri R.
      • Amanzada A.
      • et al.
      Gall bladder wall thickening as non-invasive screening parameter for esophageal varices - a comparative endoscopic - sonographic study.
      ,
      • Petzold G.
      • Tsaknakis B.
      • Bremer S.C.B.
      • et al.
      Evaluation of liver stiffness by 2D-SWE in combination with non-invasive parameters as predictors for esophageal varices in patients with advanced chronic liver disease.
      ,
      • Shehata N.M.
      • AbdelAziz A.A.
      • Abd El-Megid M.
      • Hafez Y.M.
      Evaluation of the gallbladder wall thickening as a non-invasive predictor of esophageal varices in cirrhotic patients.
      • Afifi M.
      • Rizk M.
      • Hussein A.
      Gall bladder wall thickness as non-invasive predictor of oesophageal varices in cirrhotic patients.
      • Wang J.
      • Wei W.
      • Duan Z.
      • et al.
      Development and validation of a nomogram for predicting varices needing treatment in compensated advanced chronic liver disease: a multicenter study.
      • de Alcantara R.V.
      • Yamada R.M.
      • Cardoso S.R.
      • de Fátima M.
      • Servidoni C.P.
      • Hessel G.
      Ultrasonographic predictors of esophageal varices.
      that reported estimates of GBWT in predicting EV were included in this DTA meta-analysis. Figure 1 shows the flow diagram for literature search and study selection.
      Figure 1
      Figure 1Prisma flow diagram for the included studies. PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only. From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. doi: 10.1136/bmj.n71. For more information, visit: http://www.prisma-statement.org/.
      Characteristics of included studies are summarized in Table 1. Four studies were conducted in Asia, three in Europe, three in Africa, and two in South America.
      Table 1Characteristics of the Included Studies.
      Author (year)CountryDesignGender (male/female)Age (years)Total number
      Group with varicesControlsGroup with varicesControls
      Begum 2012BangladeshCross-sectional study38/23(34–69)61
      Shehata 2021EgyptCross-sectional study39/2143/17(40–68)
      Stands for range.
      (46–70)
      Stands for range.
      120
      De Alcantara 2013BrazilCross-sectional study22/31(1–20)
      Stands for range.
      Patient with EHPVO (11 months −19 y)
      Stands for range.
      53
      Elkerdawy 2021EgyptCross-sectional study38/3220/15Median age 51 years105
      Ersoz 2021TurkeyCross-sectional study65
      Khan 2020PakistanProspective/observational cohort study52/2848/32(46.28 ± 8.74)
      Stands for mean and SD.
      (45.84 ± 9.32)
      Stands for mean and SD.
      160
      Petzold 2019GermanyRetrospective cohort study61/39(56.1 ± 12.9)
      Stands for mean and SD.
      100
      Richter 1992GermanyComparative cross sectional study34/2534/25(10–77)
      Stands for range.
      (11–80)
      Stands for range.
      118
      Tsaknakis 2018GermanyRetrospective cohort study74%/26%47%/53%(57 ± 13)
      Stands for mean and SD.
      (57 ± 14)
      Stands for mean and SD.
      192
      MARTINS 2000BrazilCross-sectional study12/108/10(18–44)
      Stands for range.
      (18–36)
      Stands for range.
      40
      Wang 2021ChinaRetrospective cohort study134/61(51.8 ± 10.9)
      Stands for mean and SD.
      195
      Afifi 2022EgyptCross-sectional study36/1423/27(56.5 ± 8.1)
      Stands for mean and SD.
      (55.6 ± 8.1)
      Stands for mean and SD.
      100
      EHPVO, extrahepatic portal vein obstruction.
      a Stands for range.
      b Stands for mean and SD.
      The studies were conducted from 1992 to 2022. Seven studies were comparative cross-sectional studies, three were retrospective cohort, one was a prospective observational cohort, and one was a case-control study. All the studies measured the anterior wall of the gallbladder body. They used different cut-off for GBWT to be considered abnormal as illustrated in Table 2. Among the nine studies included in the meta-analysis, the control groups of seven studies were CLD patients without EV, while in one study, they were healthy controls.
      • Richter J.
      • Monteiro Eda S.
      • Braz R.M.
      • et al.
      Sonographic organometry in Brazilian and Sudanese patients with hepatosplenic schistosomiasis mansoni and its relation to the risk of bleeding from oesophageal varices.
      Table 2Data for DTA Studies.
      studyCut off valuesensitivityspecificityPPVNPV
      Dealcantara2013≥4.35 mm60%90%85.7%69.2%
      Tsaknakis 2018≥4 mm46%89%70%73%
      Petzold 20193.07 mm68.6%77.6%80%70.4%
      Elkerdawy 20213.1 mm54.29%97.14%97.40%51.50%
      Shehata 20214 mm82%77%78%81%
      Wang2021(training cohort)3.55 mm88.6%54.7%47.7%91.1%
      Wang2021(validation cohort)3.55 mm91.7%37.5%52.4%85.7%
      Afifi 20223.95929586.797.1
      DTA, diagnostic test accuracy; PPV, positive predictive value; NPV, negative predictive value.

      Quality of Studies

      The results of risk of bias assessments are described in Appendices 2, 3, and 4. Of 11 studies judged by NIH tool, 4 were of good quality, 5 were of fair quality, and 2 were of poor quality mostly due to unclear definitions of exposure and outcome measures, lack of blinding to the outcome, and non-adjustment or measurement of potential confounders. Following the NOS tool, the single case-control study was of good quality. Of seven studies judged by the QUADAS-2 tool, three studies had high risk of bias in terms of patient selection. Most of the studies did not provide clear information regarding blinding of the interpreter of the index test to results of the reference standard or blinding of the interpreter of the reference standard results to results of the index test.

      Data Analysis

      Gallbladder Thickness in EV Patients vs. Controls

      Nine studies with 1092 participants were included; all reported GBWT measurements were significantly larger in EV patients compared with the control group. The mean difference between the two groups was 1.86 mm (95% CI 1.36–2.36; I2 98%; P-value <0.01) with high heterogeneity between the studies, as shown in Figure 2.
      Figure 2
      Figure 2Meta-analysis comparing the mean GBWT between the group with EV and group without EV.

      Diagnostic Test Accuracy Meta-analysis for GBWT

      Seven studies reported data for the sensitivity and specificity of GBWT for prediction of EV. The pooled sensitivity was 0.68 (95% CI, 0.63–0.73), the pooled specificity was 0.82 (95% CI, 0.78–0.86), the pooled PLR was 4.53 (CI 95% 2.12, 9.67), the pooled NLR was 0.35 (95% CI 0.23, 0.52), and the pooled diagnostic odds ratio was 15.32 (95% CI 6.93, 33.85) as shown in Figure 3. Figure 4 shows the summary ROC plot that represents the scatterplot of (1-specificity) against sensitivity with an AUC of 0.86 and Q∗ = 0.80. High heterogeneity was present in the pooled sensitivity, specificity, positive LR, and negative LR.
      Figure 3
      Figure 3Sensitivity, specificity, NLR, and PLR of GBWT for prediction of EV.
      Figure 4
      Figure 4DOR and sROC of GBWT for prediction of EV.

      Threshold and Meta-regression Analysis

      We performed threshold analysis to evaluate the source of heterogeneity if it was due to different cut-off values. The Spearman correlation coefficient was 0.595 (P-value = 0.120), indicating insignificant correlation, and the threshold effect could not play a role in the heterogeneity of estimates. Further, we conducted a regression analysis to address the source of the heterogeneity that showed significant correlation with the study design (coefficient 1.126; P-value = 0.04).

      Sensitivity and Leave One Out Meta-analysis

      Sensitivity and leave one out meta-analyses were done for all conducted meta-analyses to evaluate the effect of each study on pooled results. It showed that no single study influenced the pooled results, and the heterogeneity did not change significantly as shown in Figure 5.
      Figure 5
      Figure 5Leave-one-out meta-analysis for meta-analysis comparing the mean GBWT.

      Studies Included in the Systematic Review

      The study by Martins et al.
      • Martins R.D.
      • Szejnfeld J.
      • Lima F.G.
      • Ferrari A.P.
      Endoscopic, ultrasonographic, and US-Doppler parameters as indicators of variceal bleeding in patients with schistosomiasis.
      had no healthy controls but divided the patients diagnosed with Schistosomiasis and EV into two groups according to previous history of variceal bleeding (total 40 patients, 18 in group 1 and 22 in group 2). The mean GBWT was 6.9 mm (±3) in patients without history of variceal bleeding (group 1) and 6.2 mm (±3) in patients with history of variceal bleeding (group 2).
      Previous study
      • Wang J.
      • Wei W.
      • Duan Z.
      • et al.
      Development and validation of a nomogram for predicting varices needing treatment in compensated advanced chronic liver disease: a multicenter study.
      created a nomogram based on routine tests to detect EV in compensated advanced CLD patients; the median GBWT was 4 mm (IQR 2.50–5.60) in a total of 168 patients. We summarized the comparative tabulated data with other non-invasive tests that predict EV
      • Sami S.S.
      • Harman D.
      • Ragunath K.
      • Böhning D.
      • Parkes J.
      • Guha I.N.
      Non-invasive tests for the detection of oesophageal varices in compensated cirrhosis: systematic review and meta-analysis.
      in Appendix 5.
      Two studies
      • Wang J.
      • Wei W.
      • Duan Z.
      • et al.
      Development and validation of a nomogram for predicting varices needing treatment in compensated advanced chronic liver disease: a multicenter study.
      ,
      • Martins R.D.
      • Szejnfeld J.
      • Lima F.G.
      • Ferrari A.P.
      Endoscopic, ultrasonographic, and US-Doppler parameters as indicators of variceal bleeding in patients with schistosomiasis.
      excluded patients with ascites, and two studies
      • Richter J.
      • Monteiro Eda S.
      • Braz R.M.
      • et al.
      Sonographic organometry in Brazilian and Sudanese patients with hepatosplenic schistosomiasis mansoni and its relation to the risk of bleeding from oesophageal varices.
      ,
      • Ersoz G.
      • Ozutemiz O.
      • Akarca U.S.
      • Yilmaz M.
      • Karasu Z.
      • Batur Y.
      Gallbladder wall thickening as a sign of esophageal varices in chronic liver disease.
      reported that the presence of ascites was not correlated to GBWT. While two studies
      • Tsaknakis B.
      • Masri R.
      • Amanzada A.
      • et al.
      Gall bladder wall thickening as non-invasive screening parameter for esophageal varices - a comparative endoscopic - sonographic study.
      ,
      • Afifi M.
      • Rizk M.
      • Hussein A.
      Gall bladder wall thickness as non-invasive predictor of oesophageal varices in cirrhotic patients.
      reported that ascites can be independent predictor for EV and GBWT, respectively, as shown in Appendix 6.
      A previous study
      • Petzold G.
      • Tsaknakis B.
      • Bremer S.C.B.
      • et al.
      Evaluation of liver stiffness by 2D-SWE in combination with non-invasive parameters as predictors for esophageal varices in patients with advanced chronic liver disease.
      reported no significant difference between compensated and decompensated chronic liver disease among EV patients; however, many studies reported that GBWT positively correlated with varices size.
      • Elkerdawy M.A.
      • Ahmed M.H.
      • Zaghloul M.S.
      • Haseeb M.T.
      • Emara M.H.
      Does gallbladder wall thickness measurement predict esophageal varices in cirrhotic patients with portal hypertension?.
      ,
      • Begum S.A.
      • Saibal A.A.
      • Das K.
      • et al.
      Thickening of gallbladder wall in chronic liver disease - a marker for esophageal varices.
      ,
      • Afifi M.
      • Rizk M.
      • Hussein A.
      Gall bladder wall thickness as non-invasive predictor of oesophageal varices in cirrhotic patients.
       In addition, they reported a significant increased GBWT was associated with advanced varices (grades III and IV) when compared with nonadvanced varices (grades I and II).

      Discussion

      Chronic liver disease is the 11th driving cause of death in adults in the United States. The development of EV and variceal hemorrhage is a common complication in CLD patients and is associated with higher mortality and morbidity.
      • Cheemerla S.
      • Balakrishnan M.
      Global epidemiology of chronic liver disease.
      This indicates the importance of primary prevention by screening for the EV presence. The current guidelines recommend EGD for the screening and diagnosis of EV.
      • Richardson E.
      • Arastu S.
      • Halegoua-DeMarzio D.
      PRO: esophagogastroduodenoscopy is the preferred modality to screen for the diagnosis of esophageal and gastric varices when the diagnosis of cirrhosis is made.
      However, the EGD is costly and invasive with potential complications.
      • Spiegel B.M.
      • Targownik L.
      • Dulai G.S.
      • Karsan H.A.
      • Gralnek I.M.
      Endoscopic screening for esophageal varices in cirrhosis: is it ever cost effective?.
      ,
      • Spiegel B.M.
      • Esrailian E.
      • Eisen G.
      The budget impact of endoscopic screening for esophageal varices in cirrhosis.
       In the present meta-analysis, we evaluated GBWT utility as a non-invasive tool in the prediction of EV in CLD patients. Previous studies evaluated the predictive value of different non-endoscopic parameters for EV.
      • Ying L.
      • Lin X.
      • Xie Z.-L.
      • Hu Y.-P.
      • Shi K.-Q.
      Performance of platelet count/spleen diameter ratio for diagnosis of esophageal varices in cirrhosis: a meta-analysis.
      • Pu K.
      • Shi J.-H.
      • Wang X.
      • et al.
      Diagnostic accuracy of transient elastography (FibroScan) in detection of esophageal varices in patients with cirrhosis: a meta-analysis.
      • Qu Y.
      • Li T.
      • Ye Q.
      • Zhang L.
      • Wang L.
      A beginning or the end? A meta-analysis to assess the diagnostic accuracy of transient elastography for the prediction of esophageal varices.
      This is the first meta-analysis to study the predictive value of GBWT by ultrasound for the diagnosis of EV among CLD patients. Measurement of GBWT in clinical practice is cheap and non-invasive in clinical practice. Previous studies showed that the GBWT is correlated with the portal hemodynamics parameters and positive correlation with portal vein diameter.
      • Li C.
      • Yang Z.
      • Ma E.
      • Liu Y.
      [Analysis of the correlation between the degree of GBWT and hemodynamic changes of portal vein system].
      This observation indicates the ability to predict the EV by GBWT and is consistent with our data that showed the pooled sensitivity is 0.73 (95% CI, 0.69–0.77), the pooled specificity is 0.71 (95% CI, 0.68–0.75), and an AUC of 0.86. The development of GBWT is similarly correlated with serum-ascites albumin gradient (SAAG).
      • Colli A.
      • Cocciolo M.
      • Buccino G.
      • et al.
      Thickening of the gallbladder wall in ascites.
      Wang et al. (8) discussed the multi factors affecting the development of GBWT in CLD patients, and they suggested portal hypertension played a role in the GBWT. This can be explained by that the gallbladder venous blood is drained via small veins that terminate in the portal venous circulation. Furthermore, several disorders cause thickening of the gallbladder wall including cholecystitis.
      • Saverymuttu S.H.
      • Grammatopoulos A.
      • Meanock C.I.
      • Maxwell J.D.
      • Joseph A.E.
      Gallbladder wall thickening (congestive cholecystopathy) in chronic liver disease: a sign of portal hypertension.
      ,
      • Loreno M.
      • Travali S.
      • Bucceri A.M.
      • Scalisi G.
      • Virgilio C.
      • Brogna A.
      Ultrasonographic study of gallbladder wall thickness and emptying in cirrhotic patients without gallstones.
      In comparison to previous studies, the current meta-analysis shows GBWT had higher accuracy values than those observed for liver stiffness in diagnosis of EV the AUC for the liver stiffness is 0.81 in any varices and 0.72 in the prediction of large varices. Moreover, the spleen stiffness was 0.75 in the prediction of severe varices.
      National Heart, Lung, and Blood Institute
      Study Quality Assessment Tools.
       A previous meta-analysis also showed evidence, supporting the utilization of spleen stiffness and LS-spleen diameter to platelet ratio score in the prediction of EV in CLD patients.
      • Manatsathit W.
      • Samant H.
      • Kapur S.
      • et al.
      Accuracy of liver stiffness, spleen stiffness, and LS-spleen diameter to platelet ratio score in detection of esophageal varices: systemic review and meta-analysis.
      Deng et al. discussed the diagnostic value of computed tomography (CT), which had the highest sensitivity, specificity, and AUC. However, the risk of radiation, risk of allergic reactions from the contrast, and contraindication in patients with hyperthyroidism and renal insufficiency limit its use.
      • Deng H.
      • Qi X.
      • Guo X.
      Computed tomography for the diagnosis of varices in liver cirrhosis: a systematic review and meta-analysis of observational studies.
      Moreover, previous study discussed the limitation of CT due to the low quality of CT images; this limits the diagnosis of EV.
      • Lipp M.J.
      • Broder A.
      • Hudesman D.
      • et al.
      Detection of esophageal varices using CT and MRI.
      This present study showed a difference between the cut-off values across the studies that need independent validation in prospective studies for the threshold 3.1 mm the higher AUC across studies. We performed the Spearman correlation of sensitivity and specificity to measure the threshold analysis of the different cut-off values and the effects on the heterogeneity of the included studies. The correlation coefficient was: 0.595; P-value = 0.121, which indicated the different cut-off values were not one of the sources of the heterogeneity in the analysis.
      It is also worth mentioning that the thickened gallbladder wall in patients with ascites is highly predictive for the diagnosis of portal hypertension-induced ascites. In a study by Mohammadi et al.,
      • Mohammadi A.
      • Ghasemi-Rad M.
      • Mohammadefar M.
      Differentiation of benign from malignant induced ascites by measuring gallbladder wall thickness.
      the GBWT in those with known ascites was significantly higher in those with portal hypertension compared with those with peritoneal carcinomatosis which confirm that development of ascites and GBWT are associated with a higher portal hypertension. While Colli et al.
      • Colli A.
      • Cocciolo M.
      • Buccino G.
      • et al.
      Thickening of the gallbladder wall in ascites.
      suggested that the gallbladder wall thickening should be considered a valuable sign of transudative ascites and of portal hypertension whatever its cause.
      Previously, hypoalbuminemia was thought to be the only mechanism for the increase of GBWT in CLD patients, but the increase of GBWT can occur in the absence of hypoalbuminemia or ascites. It can also be explained by portal hypertension causing congestion in the gallbladder wall. Therefore, many studies that explored the role of portal hypertension in GBWT excluded patients with hypoalbuminemia or divided them into subgroups according to albumin levels
      • Ersoz G.
      • Ozutemiz O.
      • Akarca U.S.
      • Yilmaz M.
      • Karasu Z.
      • Batur Y.
      Gallbladder wall thickening as a sign of esophageal varices in chronic liver disease.
      ,
      • Shehata N.M.
      • AbdelAziz A.A.
      • Abd El-Megid M.
      • Hafez Y.M.
      Evaluation of the gallbladder wall thickening as a non-invasive predictor of esophageal varices in cirrhotic patients.
      or performed a comparison between patients with equal albumin level.
      • Elkerdawy M.A.
      • Ahmed M.H.
      • Zaghloul M.S.
      • Haseeb M.T.
      • Emara M.H.
      Does gallbladder wall thickness measurement predict esophageal varices in cirrhotic patients with portal hypertension?.

      Limitation

      The main challenge in our study is the presence of high heterogeneity which may be explained by different ultrasound devices, causes of EV and CLD, different populations, and variability in the study designs. However, to overcome this limitation, we used random effect models which consider the level of heterogeneity on pooling the overall effect, and we performed a leave-one-out meta-analysis to show the effect of every single study; we did not find a single study influencing the heterogeneity nor the pooled results, and threshold analysis which did not show the contribution of the different cut-off values to the heterogeneity; this is consistent with previous DTA meta-analysis used to predict the EV.
      • Pu K.
      • Shi J.-H.
      • Wang X.
      • et al.
      Diagnostic accuracy of transient elastography (FibroScan) in detection of esophageal varices in patients with cirrhosis: a meta-analysis.
      Following strategies suggested by Cochrane book part two 9.5.3 to explore the heterogeneity, we performed a meta-regression analysis for potential covariates with available data that can be source of heterogeneity like: year of publication, country, and design of the included studies; we found significant correlation with the design of the studies (coefficient 1.126; P-value = 0.04); however, there was no significant correlation with other covariates.

      Recommendation for Future Research

      The present meta-analysis showed that GBWT is a valid non-invasive screening tool for the prediction of EV. More high-quality studies are needed with a large sample size to indicate the diagnostic performance as it is a simple, widely available parameter. Building a new model for the prediction of EV and risk of hemorrhage using a simple non-invasive parameters such as GBWT would be helpful.

      Credit authorship contribution statement

      Anas Elgenidy: Design of the study, data analyses, and manuscript writing.
      Ahmed M.Afifi: Design of the study, data analyses, manuscript writing and supervision.
      Prasun K. Jalal: Design of the study, data analyses, manuscript writing and supervision.

      Conflicts of interest

      The authors have none to declare.

      Acknowledgements

      None.

      Funding

      No financial support was used for the present work.

      Ethical approval and consent to participate

      Not applicable.

      Consent for publication

      Not applicable.

      Availability of data and materials

      The data are available from the corresponding author upon reasonable request.

      Appendix A. Supplementary data

      The following are the supplementary data to this article:

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