The high variceal rebleeding rate could exaggerate the morbidity and mortality burden on cirrhotic patients, so meticulous follow-up with an optimum prediction of rebleeding with proper preventive measures are mandatory for those patients to mitigate this devastating complication and increase survival [1,2,3,4,5,6,7]. This assumption of the deleterious effects of variceal rebleeding was taken as a rationale by many studies for the exploration of the possible predictor factors for this risk with wide variable results [8,9,10,11,12,13]. In this respect, we tried searching for the most independent predictor factors that may increase the hazard of early variceal rebleeding in cirrhotic patients after successful endoscopic control of the first episode of variceal bleeding. In our study, we took into consideration the most relevant routine laboratory and radiological criteria that are closely related to pathogenesis and development of EV in liver cirrhosis, as well as the endoscopic variceal criteria as regards its severity and bleeding risk signs and at the same time the type of endoscopic modality of variceal bleeding control.
As regards the underlying baseline liver functions, we found that higher Child-Pugh score, hypo-albuminemia, hyper-bilirubinemia, and lower levels of prothrombin concentration were significant predictors for early variceal rebleeding; however, the Child-Pugh score was found to be the most independent significant predictor factor using multivariate analysis (sig = 0.001 and OR = 1.661,). In accordance with our results, many reports identified that early variceal rebleeding rate significantly increases in higher Child-Pugh scores than lower scores [17, 18]. We could explain this finding, as the Child-Pugh score is a surrogate parameter for the underlying liver cell functions that are deteriorated in accordance to the progression of the underlying liver cirrhosis which is considered as the leading cause of portal hypertension [5, 7].
After multivariate analysis of other laboratory criteria for our participants, we found that thrombocytopenia was the only independent significant predictor for variceal rebleeding. This finding is confirmed by the results of previous reports that identified the possible role of thrombocytopenia in the prediction of portal hypertension and esophageal varices in patients with liver cirrhosis [19, 20].
The univariate regression analysis of the baseline radiological criteria of our participants identified that splenomegaly, increased ascites, increased PVD, and decreased PVV were significantly associated with increased risk of early variceal rebleeding. However, by multivariate analysis, we found that PVV was the only independent significant predictor for the risk of variceal rebleeding. The reliability of PVV as a non-invasive tool for the prediction of esophageal varices in cirrhotic patients was confirmed previously in many reports [21, 22]. Consequently, we could suggest that PVV may be used not only in the prediction of esophageal varices in cirrhotic patients but also in the prediction of early variceal rebleeding in those patients. However, to our knowledge, there were no studies that discussed the correlation between PVV and the risk of early variceal rebleeding of esophageal varices.
As regards the endoscopic variceal criteria of our participants, the univariate regression analysis showed that variceal grading, variceal location, and red color signs were significantly associated with the risk of rebleeding. However, the multivariate regression analysis identified that the most independent significant endoscopic variceal criteria were EV grading and variceal red color sign. These results are in agreement with many previous reports that found a significant association of variceal rebleeding with variceal size [23,24,25] and variceal red color sign or nipple sign [24,25,26].
In summary, after univariate and multivariate analysis of all our potential predictors for variceal rebleeding, we found that the only independent significant predictors were higher levels of the Child-Pugh score, thrombocytopenia, decreased PVV, larger variceal size, and the presence of variceal red color risk sign. All of these five independent significant predictors are related to pathophysiology or the complications of portal hypertension and EV in cirrhotic patients [7, 27].
We used the multivariate regression coefficients of those five independent significant predictors to derive a new early variceal rebleeding risk (EVRR) score that revealed a significant discriminatory performance, and two cutoff points (≤ 0.10 and ≥ 0.90) were identified; the 1st cutoff point was selected to rule out the possibility of occurrence of early variceal rebleeding for values equal or below it and the 2nd cutoff point was selected to rule in the possibility of occurrence of early variceal rebleeding for values equal or above it. We graded the EVRR score to 3 grades using those two cutoff points for risk stratification: values ≤ 0.10 to identify EVRR grade 1 with mild risk, values ≥ 0.90 to identify EVRR grade 3 with high risk, and EVRR grade 2 with moderate risk for remaining values, the pairwise comparisons of rebleeding free survival function between the different risk grades of EVRR identified statistically significant difference. However, this proposed score should be externally validated later in large prospective studies.
We found some aspects of limitations in our study, one of them is the single center enrollment that may limit the study generalizability, and the presence of more than one operator for both endoscopy and abdomen ultrasound that may increase the inter-observer variability in values of predictors; however, this limitation was mitigated through their highly trained experience and using of advanced equipment. Other aspects of limitations, as we did not take into consideration the medical treatment that may be prescribed for variceal patients after endoscopy and during the follow-up data like non-selective beta-blockers and proton pump inhibitors, however, these medical treatments were prescribed to most of our patients.