Introduction

Compensated advanced chronic liver disease (cACLD) defines patients at risk for hepatic complications, while the presence of clinically significant portal hypertension (CSPH) identifies the target population for prevention of hepatic decompensation (1). By liver stiffness measurement (LSM) via vibration-controlled transient elastography (VCTE), it is possible to non-invasively identify these conditions, however, its availability is usually limited to tertiary care. The currently necessary dependence on VCTE/referral pathways may hamper the identification of cACLD and/or CSPH in the community.

Aims & Methods

Thus, we aimed to develop an algorithm based on routine laboratory parameters to (i) identify cACLD patients (via FIB-4) and (ii) to subsequently rule-in or rule-out CSPH using the von Willebrand factor antigen/platelet count ratio (VITRO).
FIB-4 cohort: All patients with suspected cACLD undergoing LSM and FIB-4 assessment at the Medical University Vienna between 2007-2021 were characterized and followed-up for development of hepatic decompensation in order to determine a FIB-4 cut-off reflecting cACLD.
VITRO cohort: cACLD patients (diagnosed by the established FIB-4 cut-off) with hepatic venous pressure gradient (HVPG) measurement were analysed in order to determine VITRO cut-offs for ruling-in/ruling-out CSPH with satisfactory sensitivity/specificity (>90%).

Results

FIB-4 cohort: 6182 patients were followed-up for a median of 54.6 months. First hepatic decompensation occurred in 3.4% (n=211) of patients. Of note, both LSM (area under the curve [AUC] 0.90; 95% confidence interval [95%CI]: 0.86-0.92) and FIB-4 (AUC 0.91; 95%CI: 0.88-0.94) exhibited excellent accuracy in predicting hepatic decompensation within 2 years of follow-up. FIB-4 ≥1.75 corresponded to LSM ≥10kPa and was thus determined as a cut-off for identifying cACLD. cACLD could be ruled-out in 72% of patients with this cut-off. In patients with FIB-4 <1.75 cumulative incidence of hepatic decompensation at 5 years of follow-up was negligible (0.03%).
VITRO cohort: 317 cACLD patients with a CSPH prevalence of 62.8% (n=199/317) were included. VITRO showed a good performance for CSPH diagnosis (AUC 0.85; 95%CI: 0.80-0.89) that was comparable to LSM (AUC 0.85; 95%CI: 0.81-0.89; DeLong-Test: p=0.903) and to the ANTICIPATE model (AUC 0.89; 95%CI: 0.86-0.93; p=0.109). VITRO <1.0 ruled-out (prevalence: 11.4%; sensitivity 97.5%) and VITRO ≥2.5 ruled-in CSPH (prevalence: 41.6%; specificity 90.6%). Importantly, these diagnostic indices were comparable to the Baveno VII cut-offs for ruling-out (i.e. LSM ≤15kPa & PLT ≥150G/L; prevalence: 10.1%; sensitivity: 99.0%) and ruling-in CSPH (i.e. LSM ≥25kPa; prevalence: 44.2%; specificity: 89.0%).

Conclusion

FIB-4 ≥1.75 identifies cACLD (defined by risk rather than stage, according to Baveno VII) and VITRO <1.0/≥2.5 rules-out/rules-in CSPH with a similar diagnostic accuracy as criteria based on LSM. Simple laboratory tests available in primary/secondary care may broaden the access to risk stratification and facilitate early intervention.

References

1. de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C. Baveno VII - Renewing consensus in portal hypertension. J Hepatol 2022;76:959-974.

Introduction

Helicobacter pylori（H.pylori） is a major risk factor for gastric cancer. Our previous study found that activin A receptor type I (ACVR1) plays an important role in the pathogenesis of gastric mucosal lesions caused by Helicobacter pylori. Meanwhile, transcriptome data showed that ACVR1 was negatively correlated with POLD1, the gene encoding the catalytic subunit of EUkaryotic DNA polymerase (Pol δ) P125. However, the specific roles of ACVR1 and ACVR1 in H.pylori carcinogenesis remain unclear. This study investigated the molecular mechanism and potential association between H.pylori, ACVR1 and POLD1 in gastric cancer.

Aims & Methods

Gastric cancer cells, human tissue and mouse model were used in this study. We used helicobacter pylori infection models in vitro and in vivo, and Western blot, QRT-PCR, immunofluorescence, COIP, CCK8, Transwell and other tests for molecular, mechanism and function studies.To explore the role of Helicobacter pylori in DNA damage repair through ACVR1.

Results

Transcriptome data showed a negative correlation between ACVR1 and POLD1 expression. In vitro results showed that Hp infection could up-regulate the expression of ACVR1 and γ-H2AX, and decrease the expression of POLD1. After the deletion of ACVR1, the expression of POLD1 was increased. The expression of POLD1 decreased when ACVR1 was overexpressed. By predicting transcription factors, it was found that IRF3 could regulate the transcription of POLD1, and Hp infection could down-regulate the expression of IRF3, which was related to the virulence factor CagA. In addition, interference with the expression of POLD1 can up-regulate the expression of γ-H2AX, and inhibit cell proliferation, invasion and migration.

Conclusion

In summary, our study found that the ACVR1-IRF3-POLD1 signaling axis plays an important role in the process of Helicobacter pylori infection causing gastric cancer, and the ACVR1-IRF3-POLD1 axis can promote the occurrence of DNA damage while inhibiting the biobehavioral function of tumor cells.