Introduction

Esophageal and gastric variceal bleeding is a life-risk complication of portal hypertension, with a high mortality. Recently, the number of patients with unexplained portal hypertension is gradually increasing¹. Non-cirrhotic portal hypertension caused by pre-hepatic/post-hepatic causes can also cause esophageal and gastric varices, of which the clinical diagnosis and treatment are still difficult². Oxaliplatin (Op) is a first-line drug in chemotherapy regimens for many kinds of cancers³, while the incidence of portal hypertension (PH)-related symptoms during follow-up of Op-treated patients without prior liver disease is increasing⁴. Chronic liver damage and portal hypertension caused by platinum-based drugs have an insidious onset and almost half of them are diagnosed due to the emergency treatment for esophageal and gastric variceal bleeding, which is highly dangerous and affects the long-term survival of patients⁵. To date, oxaliplatin-related PH studies are mainly clinical reports, and the underlying mechanisms are unclear.

Aims & Methods

We aimed to explore the pathology, mechanisms and key molecular players and potential pharmacological prevention of Op-induced PH. Gene expression profiles related to Op treated vs normal human livers were obtained from the GEO database, to identify key molecules and pathways via differentially expressed genes (DEG). OP-induce PH was induced in rats and liver transcriptome profiles were compared with the human samples, and key signatures confirmed by PCR. Since main Op-induced signatures were due to hepatocytes, human hepatocytes LO2 were treated with Op, and molecular responses measured in these cultures and in cultures of primary human liver sinusoidal endothelial cells (HHSEC) exposed to LO2-conditioned media.

Results

Totally, 19 Op-treated and 5 Op-treated rats were analyzed with 5 and 3 controls, respectively. Liver samples from Op-treated patients showed apparent hepatic sinusoidal dilatation. PH was induced by a 6-week Op treatment in rats, with sinusoidal endothelial activation and perivenous monocyte-macrophage infiltration, while a classical sinusoidal obstructive syndrome was missing. Hyaluronan synthase 2 (HAS2) and prominently the ERK pathway were upregulated after Op treatment in both rats and patients. Op-treated LO2-hepatocytes showed the activation of ERK pathway, and the up-regulation of HAS2; Co-culture of HHSEC and Op-treated LO2-hepatocytes showed that mediators released from LO2 cells induced HHSEC activation: up-regulated von Willebrand and tissue factor, increased migration, and activation of the ERK pathway. Notably, HHSEC migration was also increased after hyaluronic acid (HA) treatment, confirming an important role of HAS2 in Op-induced pathology.

Conclusion

Activation of the MAPK/ERK cascade is central to Op-induced PH. This pathway is implicated in the upregulation of HAS2 in hepatocytes, which releases HA, which activaties sinusoidal endothelial cells, resulting in LSEC damage and subsequent portal hypertension.

References

1. Biecker E. Portal hypertension and gastrointestinal bleeding: diagnosis, prevention and management. World J Gastroenterol. 2013;19(31):5035-50.
2. Gioia S, Nardelli S, Ridola L, Riggio O. Causes and Management of Non-cirrhotic Portal Hypertension. Current Gastroenterology Reports. 2020;22(12).
3. Zhang, C., et al., Platinum-based drugs for cancer therapy and anti-tumor strategies. Theranostics, 2022. 12(5): p. 2115-2132.
4. Gioia S, Di Martino M, Minozzi M, Nardelli S, Cortesi E, Riggio O. Incidence of portal hypertension in patients exposed to oxaliplatin. Dig Liver Dis. 2019;51(9):1348-50.
5. Huang, X., et al., Endoscopic treatment of gastroesophageal variceal bleeding after oxaliplatin-based chemotherapy in patients with colorectal cancer. Endoscopy, 2020. 52(9): p. 727-735.

Introduction

Gastroesophageal varices are present in approximately 50% of cirrhotic patients¹. The cirrhosis-related age-standardized mortality is high². Gastroesophageal variceal bleeding is a medical emergency with a mortality rate of approximately 10-20% at six weeks¹, and rebleeding incidence ranged from 32% to 84%³, and even higher, around 90%, in patients receiving no antiviral therapy⁴. Endoscopic variceal ligation (EVL) and endoscopic variceal obliteration (EVO) with cyanoacrylate are recommended for patients with acute variceal bleeding⁵, but both treatments have no impact on portal pressure⁶. Portal hypertension is the primary pathophysiological mechanism underlying gastroesophageal varices. Non-selective beta-blockers (NSBBs) induce vasodilation by targeting beta-receptors on blood vessels and the heart, reduce cardiac output through negative inotropic effects, thereby reducing portal blood flow and associated portal pressure^{7, 8}. Gastroesophageal varices type 1 (GOV1) and type 2 (GOV2) are varices in direct continuity from the esophagus to the stomach (lesser and greater curvatures, respectively)⁹. We chose EVL after EVO for treatment of GOV1 and GOV2, which tended to have a better secondary prophylactic effect according to our clinical experience. However, no prior research has evaluated the effect of additional NSBB under these circumstances. It remains unclear whether the addition of NSBB provides further benefit after combined use of tissue adhesive and endoscopic variceal ligation for bleeding gastroesophageal varices.

Aims & Methods

We retrospectively analyzed cirrhotic patients (mainly due to hepatitis B and C) who received endoscopic combined treatment of gastroesophageal varices and were assigned or not to NSBB treatment as a second prophylaxis. Subanalysis was done for ascites, portal vein thrombosis, splenectomy, and Child-Pugh grade. 5-year overall survival and rebleeding rates were compared between treatment groups.

Results

A total of 490 patients were analyzed, and 130 patients received additional NSBB treatment. Although the additional NSBB treatment did not lead to a statistically significant difference in overall 5-year survival (Log-rank test, p = 0.133), it did reduce the 5-year rebleeding rate from 45.7% to 30.64% (Log-rank test, p = 0.002, univariate COX analysis, HR 0.57, 95% CI 0.39-0.82), consistent with the comparison after propensity score matching. Neither overall survival nor bleeding differed significantly between propranolol and carvedilol. NSBB (HR 0.54, 95% CI 0.37-0.79, p = 0.001) and splenectomy (HR 0.65, 95% CI 0.44-0.96, p = 0.030) were independent factors in reducing rebleeding, rather than improving survival, in cirrhotic patients who received combined endoscopic treatment. In patients without splenectomy, NSBB treatment improved overall survival (Log-rank test, p = 0.019, univariate COX analysis, HR 0.43, 95% CI 0.21-0.89) and reduced rebleeding rates (Log-rank test, p = 0.001, univariate COX analysis, HR 0.52, 95% CI 0.34-0.78).

Conclusion

We show for the first time that adding NSBB to combined endoscopic therapy significantly reduced recurrent variceal bleeding (GOV1 & GOV2) in cirrhotic patients, yet did not improve overall survival, except for patients without splenectomy. The addition of NSBB for patients receiving combined endoscopic treatment of gastroesophageal varices provides benefits but does not prolong overall survival.

References

1. Jakab SS, Garcia-Tsao G. Evaluation and Management of Esophageal and Gastric Varices in Patients with Cirrhosis. Clin Liver Dis 2020;24:335-50.
2. Collaborators GBDC. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol 2020;5:245-66.
3. de Franchis R, Primignani M. Natural history of portal hypertension in patients with cirrhosis. Clin Liver Dis 2001;5:645-63.
4. He L, Ye X, Ma J, et al. Antiviral therapy reduces rebleeding rate in patients with hepatitis B-related cirrhosis with acute variceal bleeding after endotherapy. BMC Gastroenterol 2019;19:101.
5. de Franchis R, Bosch J, Garcia-Tsao G, et al. Baveno VII - Renewing consensus in portal hypertension. J Hepatol 2022;76:959-74.
6. European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018;69:406-60.
7. Baiges A, Hernández-Gea V, Bosch J. Pharmacologic prevention of variceal bleeding and rebleeding. Hepatol Int 2018;12:68-80.
8. Reiberger T, Mandorfer M. Beta adrenergic blockade and decompensated cirrhosis. J Hepatol 2017;66:849-59.
9. Alqahtani SA, Jang S. Pathophysiology and Management of Variceal Bleeding. Drugs 2021;81:647-67.

Clinical Case Summary

Here we report the case of a 71-year-old man with alcohol-related gastric variceal bleeding (GVB) (50-year alcohol history, 150-200g/day) under management by endoscopic ultrasound (EUS) guided injection of coils, suggesting that the perforator embolization of intragastric varices would eventually complete obstruction of intraluminal gastric varices, leading to the era of the precision treatment of GVB.

Gastric varices are usually accompanied by porta-systemic collaterals¹. Isolated type 1 gastric varices, located in the fundus of the stomach, are a type of cardiofundal varices². Endoscopic injection of tissue adhesive (N-butyl-cyanoacrylate, CYA) is the first-line treatment, but is technically difficult with a high risk of ectopic embolization. Here we report a novel technique: EUS combined with computed tomographic angiography (CTA)-guided embolization of transmucosal cardiofundal varices, which takes advantage of EUS guidance and CTA-based radiological reconstruction of the varices, allowing visualisation of the feeding vessel of intragastric varices, significantly reducing coil consumption.

The vessel reconstruction implicated large cardiofundal varices around the stomach of this patient. We identified one transmucosal branch, and then confirmed the targeted transmucosal perforator branch supplying the complex of intragastric varices. The target gastric varices were accessed with a 19G needle, coils and cyanoacrylate were inserted through the needle into the branch under EUS. After implantation, EUS showed complete embolization of intragastric luminal varices. The CTA of the portal venous after 2 months showed the elimination of the cardiofundal varices. Follow-up endoscopy showed the gastric varix complex diminished while the esophageal varices became obvious; therefore, further endoscopic esophageal variceal ligation was performed. The complete elimination of gastric and esophageal varices was obtained after two sessions of endoscopic treatment.

References

1. Pillai AK, Andring B, Patel A, Trimmer C, Kalva SP. Portal hypertension: a review of portosystemic collateral pathways and endovascular interventions. Clin Radiol. 2015;70(10):1047-59.
2. Aleem A, Shah H. Gastric Varices. StatPearls. Treasure Island (FL) ineligible companies. Copyright © 2024, StatPearls Publishing LLC.; 2024.

Introduction

Portal hypertension is a major complication of advanced chronic liver disease (ACLD) and is associated with gastro-oesophageal varices, a leading cause of morbidity and mortality. The British Society of Gastroenterology (BSG) recommends oesophagogastroduodenoscopy (OGD) for variceal screening in all patients with cirrhosis, which could result in a high volume of unnecessary procedures. Given increasing demands on NHS services and the need for cost-effective resource allocation, strategies to reduce unnecessary endoscopy are critical.
The Baveno VI and VII consensus workshops propose non-invasive criteria to optimise variceal screening. Baveno VI suggests that patients with a liver stiffness measurement (LSM) less than 20 kPa and a platelet count greater than 150×10⁹/L can safely avoid OGD. Baveno VII further refines this by recommending non-selective beta-blocker (NSBB) therapy in patients with clinically significant portal hypertension (CSPH), defined as LSM greater than 25 kPa, thereby eliminating the need for screening endoscopy in this group. For patients not clearly stratified by Baveno VI or VII criteria, splenic stiffness measurement (SSM) offers an additional non-invasive tool to refine risk assessment. Incorporating SSM in this intermediate-risk group may further reduce the need for OGD, with recent data showing a high negative predictive value for ​ruling out high-risk varices.

Aims & Methods

We aim to quantify the reduction in endoscopy burden achieved by applying Baveno VI and VII criteria in ACLD patients.
A retrospective analysis was conducted on 1,703 patients who underwent 1,802 FibroScans between January 1, 2024, and December 31, 2024. Patients were stratified based on LSM and platelet counts into the following categories:
1. BSG Criteria: All patients with LSM ≥10 kPa requiring OGD.
2. Baveno VI Criteria: Patients with LSM <20 kPa and platelet count ≥150×10⁹/L, for whom OGD could be safely avoided.
3. Baveno VII Criteria: Patients with CSPH (LSM ≥25 kPa) recommended for NSBB therapy without the need for screening OGD.
4. Patients requiring OGD: Those not meeting Baveno VI criteria and without CSPH.

Results

Liver stiffness distribution:
• <10 kPa: 1,534 patients
• 10–14.9 kPa: 136 patients
• 15–19.9 kPa: 44 patients
• 20–24.9 kPa: 31 patients
• ≥25 kPa: 57 patients
Impact of Adopting Baveno VI and VII:
• BSG Guidelines: 274 patients (LSM ≥10 kPa) would require OGD.
• Baveno VI: 149 patients (LSM <20 kPa, platelets ≥150) could avoid OGD.
• Baveno VII: 57 patients (LSM ≥25 kPa) would be managed with NSBB, avoiding OGD.
• Total Reduction: 206 out of 274 patients (~75%) could avoid OGD.

Conclusion

Adopting Baveno VI and VII criteria would significantly reduce the need for variceal screening endoscopy in ACLD patients. By applying these thresholds, up to 75% of OGDs could be avoided, optimising NHS resources and reducing patient burden. These findings support the routine use of non-invasive risk stratification in ACLD management.

References

1. Tripathi D, Stanley AJ, Hayes PC, et al. UK guidelines on the management of variceal haemorrhage in cirrhotic patients. Gut. 2015;64(11):1680–1704. doi:10.1136/gutjnl-2015-309262
2. de Franchis R, Bosch J, Garcia-Tsao G, et al. Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015;63(3):743–752. doi:10.1016/j.jhep.2015.05.022
3. de Franchis R, Bosch J, Garcia-Tsao G, et al. Baveno VII – Renewing consensus in portal hypertension. J Hepatol. 2022;76(4):959–974. doi:10.1016/j.jhep.2021.12.022

Introduction

The European Society of Gastrointestinal Endoscopy Guideline (ESGE) suggests endoscopic variceal ligation for treating acute esophageal variceal hemorrhage, and either endoscopic cyanoacrylate injection or EVL for GOV1-specific bleeding. However, some experts propose treating GOV1 similarly to esophageal varices since varices along the lesser curvature share a similar natural history. Thus, data on endoscopic obstruction of gastric varices in GOV1 patients with esophageal variceal bleeding are limited. The efficacy of EVL for esophageal varices combined with cyanoacrylate injection for gastric varices in GOV1 appears promising.

Aims & Methods

In this multi-center retrospective cohort study, we aimed to access the efficacy of blocking gastric varices in the managing bleeding from esophageal varices in patients with GOV1.Cirrhotic patients experiencing bleeding from esophageal varices and habing GOV I gastric varices in four centers were screened. All included patients were followed up for 180 days, or until death.

Results

A total of 93 cirrhotic patients with GOV I and bleeding esophageal varices were included. Among them, 58 patients underwent endoscopic cyanoacrylate injection (ECI) for gastric varices in addition to treatment for esophageal varices (EV) treatment, while the remaining 35 patients received treatment for EV only. Kaplan-Meier analysis demonstrated that the cumulative 180-day rebleeding rate was significantly lower in the ECI plus EV treatment group (7.9%) compared to the EV treatment group (30.7%) (p=0.0031). The cumulative incidence of 180-day mortality rate was 1.9% in the ECI plus EV treatment group and 23.9% in the EV treatment group (p=0.0010). Multivariable Cox regression analysis revealed that concomitant ECI treatment was an independent protective factor against for 180-day rebleeding and overall mortality.

Conclusion

In conclusion, obstruction of gastric varices in addition to endoscopic treatment for bleeding from esophageal varices in patients with GOV 1 proved superior to endoscopic treatment alone for esophageal variceal bleeding.

References

1, de Franchis R, Bosch J, Garcia-Tsao G et al. Baveno VII - Renewing consensus in portal hypertension. J Hepatol 2022; 76: 959-974. doi:10.1016/j.jhep.2021.12.022
2, Gralnek IM, Camus Duboc M, Garcia-Pagan JC et al. Endoscopic diagnosis and management of esophagogastric variceal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy 2022; 54: 1094-1120. doi:10.1055/a-1939-4887
3, Kaplan DE, Bosch J, Ripoll C et al. AASLD practice guidance on risk stratification and management of portal hypertension and varices in cirrhosis. Hepatology 2023. doi:10.1097/hep.0000000000000647]