Small esophageal varices in compensated cirrhosis patients: to treat or not to treat?

Abstract

We would like to congratulate Wang et al. for demonstrating that adding spleen stiffness measurement to the existing Baveno-VI criteria can spare more screening gastroscopy without missing more high-risk esophageal varices (EVs) compared to the Baveno-VI criteria.[1]Wang H. Wen B. Chang X. Wu Q. Wen W. Zhou F. et al.Baveno VI criteria and spleen stiffness measurement rule out high- risk varices in virally suppressed HBV-related cirrhosis.J Hepatol. 2021; 74: 584-592Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar The definition of “low-risk varices” was potentially misleading as it also included patients without EVs. It would be interesting to also report the performance of this criteria in predicting the presence of small EVs. There is an ongoing discussion regarding the need to treat small EVs in patients with compensated cirrhosis. The current guidelines do not support primary prophylaxis of small EVs as the treatment of small EVs does not reduce the risk of variceal progression, variceal bleeding or death.[2]European Association for the study of the liverEASL Clinical practice guidelines for the management of patients with decompensated cirrhosis.J Hepatol. 2018; 69: 406-460Abstract Full Text Full Text PDF PubMed Scopus (797) Google Scholar,[3]De Franchis R. Baveno VI facultyExpanding consensus in portal hypertension: report of the BAVENO VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.J Hepatol. 2015; 63: 743-752Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar On the other hand, small EVs herald the presence of clinically significant portal hypertension (CSPH) in patients with compensated cirrhosis, who might benefit from non-selective beta-blockers (NSBBs) to prevent future decompensations.[4]Rodrigues S.G. Mendoza Y.P. Bosch J. Beta-blockers in cirrhosis: evidence-based indications and limitations.JHEP Rep. 2019; 2: 100063Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Preventing liver decompensation is an important clinically meaningful endpoint in the management of patients with CSPH.[2]European Association for the study of the liverEASL Clinical practice guidelines for the management of patients with decompensated cirrhosis.J Hepatol. 2018; 69: 406-460Abstract Full Text Full Text PDF PubMed Scopus (797) Google Scholar,[3]De Franchis R. Baveno VI facultyExpanding consensus in portal hypertension: report of the BAVENO VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.J Hepatol. 2015; 63: 743-752Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar With the intent to prevent first variceal bleeding and reduce cost, enormous efforts have been made to identify patients in whom variceal screening can be avoided without missing high-risk varices,[5]Chang P.E. Tan C.K. Cheah C.C. Li W. Chow W.C. Wong Y.J. Validation of the expanded Baveno-VI criteria for screening gastroscopy in Asian patients with compensated advanced chronic liver disease.Dig Dis Sci. 2020; ([published online ahead of print, 2020 May 21])https://doi.org/10.1007/s10620-020-06334-yCrossref Scopus (3) Google Scholar,[6]Wong Y.J. Kew G.S. Tan P.S. Chen Z. Putera M. Yip W.A. et al.Novel ABP criteria for the exclusion of high-risk varices in compensated advanced chronic liver disease.Clin Res Hepatol Gastroenterol. 2021; ([early view])https://doi.org/10.1016/j.clinre.2020.101598Crossref PubMed Scopus (1) Google Scholar principally by utilizing non-invasive modalities. However, the application of non-invasive criteria focused on excluding high-risk varices may miss a significant proportion of patients with small EVs.[7]Reiberher T. Bucsics T. Paternostro R. Pfisterner N. Rield F. Mandofer M. Small esophageal varices in patients with cirrhosis – should we treat them?.Curr Hepatol Rep. 2018; 17: 301-315Crossref PubMed Google Scholar Specifically, the risk of decompensation in patients with compensated cirrhosis and small EVs has not been well studied. To compare the risk of liver decompensation between patients with or without small EVs, we analyzed our prospectively recruited cohort of patients with compensated cirrhosis from 2013 to 2018. The primary outcome was the occurrence of liver decompensation (variceal bleeding, clinically significant ascites or overt hepatic encephalopathy [HE]). Of the 314 consecutively enrolled patients with paired liver stiffness measurement (LSM) in whom an esophago-gastroduodenoscopy had been performed, 34 were excluded based on the presence of high-risk varices (n = 17) or gastric varices (n = 17). The remaining 280 patients were included in the analysis, of whom 56 (20%) had small EVs. Cirrhosis of viral etiology was treated with antivirals and virological suppression was achieved in all cases. In addition, none of the patients with alcohol-related cirrhosis reported significant alcohol intake during the study period. Notably, patients with small EVs had a higher median LSM (26.7 kPa [IQR 21.1–43.3] vs. 17.3 kPa [IQR 13.9–24.8], p <0.001), lower mean platelet count (139x103 [SD 56 x103] vs. 174x103 [SD 68 x103], p <0.001) and lower mean serum albumin (39 g/L [SD 6 g/L] vs. 41 g/L [SD 5g/L], p = 0.014), compared to patients without EVs. We performed competing risk analysis with death as a competing event and found that the risk of decompensation remained higher among patients with small EVs (subdistribution hazard ratio 4.7, 95% CI 1.4–16.4, p = 0.015) after adjusting for albumin and model for end-stage liver disease score over a median follow-up of 36 (IQR 22–50) months (Fig. 1). While patients with small EVs are more likely to develop clinically significant ascites (small EV: 14.3% vs. 4.0%, p = 0.009), the total episodes of variceal bleeding (small EV: 2 vs. 5, p = 0.424) and overt HE (small EV: 4 vs. 3, p = 0.126) were similar, irrespective of the presence of small EVs. None of the patients in this cohort underwent liver transplantation. The application of the Baveno-VI criteria in the total cohort (n = 314) missed 3 patients with EVs (1 small EV and 2 high-risk EVs), demonstrating good sensitivity (96.7%, 95% CI 90.7–99.3%) and negative predictive value (96.6%, 95% CI 90.3–99.3%) in excluding EVs in our cohort. The major findings of our study were that: i) the Baveno-VI has good performance for the exclusion of EVs in patients with compensated cirrhosis; ii) small EVs are associated with a higher risk of liver decompensation, which is consistent with a prior study demonstrating that the presence of varices predicts a higher risk of decompensation.[8]D'Amico G. Garcia-Tsao G. Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis. A systematic review of 118 studies.J Hepatol. 2006; 44: 217-231Abstract Full Text Full Text PDF PubMed Scopus (1714) Google Scholar In the PREDESCI study, NSBBs significantly reduce the risk of liver decompensation and death (HR 0.51, 95% CI 0.26–0.97),[9]Villaneuva C. Albillos A. Genesca J. Garcia-Pagan J.C. Calleja J.L. Acaril C. et al.Beta-blocker to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomized, double-blinded, placebo-controlled trial.Lancet. 2019; 393: 1597-1608Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar thus supporting the early detection of compensated cirrhosis with CSPH so that NSBBs can be used to prevent future decompensation. While the results were exciting, it is important to remember that this study enrolled patients with CSPH diagnosed based on hepatic venous pressure gradient, which is invasive, operator-dependent, resource-intensive and not widely available. A widely available non-invasive criterion to accurately identify patients with compensated cirrhosis and CSPH remains an unmet clinical need. In summary, we demonstrated that small EVs predict a higher risk of liver decompensation, even though the short-term risk of variceal bleeding was similar to patients without EVs (Fig. 1). Rather than focusing on bleeding risk alone, our findings support the changing paradigm to consider treating small EVs to prevent future liver decompensation. The ongoing BOPPP trial (NCT03776955) is investigating the benefit of NSBBs to prevent first bleeding in patients with small EVs, with the results highly anticipated. The design or validation of future studies on the performance of non-invasive criteria to spare more screening endoscopy should incorporate clinical outcomes and consider the ability to detect both small EVs and high-risk varices. Dr Wong YJ is supported by Nurturing Clinician Scientist Scheme, Singhealth Duke-NUS Medicine Academic Clinical Program (ACP) . Study concept: WYJ. Data collection: MP, TKB. Drafting manuscript: WYJ, MP. Critical review of final manuscript: All authors. All authors declare that there is no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details. The following is the supplementary data to this article: Download .pdf (.25 MB) Help with pdf files Multimedia component 1 Baveno VI criteria and spleen stiffness measurement rule out high-risk varices in virally suppressed HBV-related cirrhosisJournal of HepatologyVol. 74Issue 3PreviewThere are no data validating the performance of spleen stiffness measurement in ruling out high-risk varices in patients with HBV-related cirrhosis under maintained viral suppression. Thus, we aimed to prospectively validate the performance of spleen stiffness measurement (cut-off 46 kPa) combined with Baveno VI criteria in ruling out high-risk varices in these patients. Full-Text PDF Reply to: “Small esophageal varices in compensated cirrhosis patients: To treat or not to treat?”Journal of HepatologyVol. 75Issue 2PreviewOn behalf of my colleagues, we thank Dr Putera et al.1 for their interest in and comment on our study.2 According to the criteria proposed by the Baveno VI Consensus Conference,3 high-risk varices (HRVs) were defined as grade 1 esophageal varices (EVs) with red signs or grade ≥2 EVs which were deemed clinically significant and required treatment in standard clinical practice. Thus, low-risk varices were described as grade <2, including no EVs or grade 1 EVs without red signs, for which bleeding risk is considered low and prophylactic therapy is deemed unnecessary. Full-Text PDF