Introduction

A transmural oxidative imbalance, mainly affecting longitudinal muscle, has been reported in the different clinical phenotypes of Diverticular Disease (DD) (Pallotta L,2022; Cappelletti M,2022) but the genesis of the oxidative stress remains to be defined. Since the central role of the mitochondria for the cell metabolism and radicals production, aim of the study is to elucidate the involvement of mitochondria alterations in the different DD clinical phenotypes in order to improve the knowledge of the DD natural history and management.

Aims & Methods

Longitudinal smooth muscle tissues and cells were isolated separately from surgical specimens of complicated stenotic DD (cDD n=5), up-stream non-occlusive colon cancer with diverticula (DIV n=5) and without diverticula (controls n=5). Oxidized proteins, thioredoxin and, succinate deidrogenase (complex II) and complex IV (cytochrome c oxidase) of mitochondrial respiratory chain were evaluated on tissues by Western Blot. Mitochondrial mass, mitochondrial ROS, mitochondrial membrane potential and glutathione (GSH) were evaluated in cells by FACS. Functional cells activity was tested by image micrometry assessing maximal contraction to acetylcholine and relaxation to VIP, before and after 24h-incubation with 14mM polyphenols (Phenolea Active Complex L). Data (mean±SE) were expressed as fold variations or % decrease from controls, *p value<0.05 considered significant.

Results

In respect to control, oxidized proteins content in longitudinal muscle was increased both in DIV (5.0*±1.1) and cDD (2.6±0.6), associated to a progressive loss of the antioxidant thioredoxin molecule (DIV:70.9%±9.2;cDD:83.3%±3.4). The oxidative status resulted associated to a loss of the mitochondrial complex II succinate deidrogenase codified by nuclear DNA (DIV:43.4%±19.7;cDD:67.9%±10.3) suggestive of the electron respiratory chain impairement. Compensatory stress mechanisms likely occurred with an increase of the complex IV cytochrome c oxidase codified by mitochondrial DNA in muscle tissue (DIV:1.1±0.77;cDD:2.3±1.7) and mitochondrial mass increase (DIV:2.4±1.2;cDD:3.7*±1.3) in cells. Radicals over production was observed mainly in cDD with a cellular increase in mitochondrial ROS (cDD:1.50±0.57) and mitochondrial membrane potential (cDD:1.4±0.3). Antioxidant GSH cellular content progressively decreased from DIV (51.9%*±9.5) to cDD (72.2%*±1.5). These oxidative alterations were associated to an impairment of functional cellular activity with a reduction of contraction (DIV:51.3%*±4.5;cDD:52.5%*±8.5) and relaxation (DIV:34.9%*±14.3;cDD:37.6%*±10.6). The prominent role of oxidative stress in these functional alterations was confirmed by the ability of a 24/h polyphenols treatment to restore GSH content (DIV:1.1±0.06;cDD:1.4±0.3) and relaxation, in both DD phenotypes.

Conclusion

Oxidative stress-driven alterations are present in longitudinal muscle in DD, independently from the clinical stage. In accordance to the severity of the pathology, mitochondrial imbalance resulted more prevalent in complicated diverticular disease. The beneficial effects of the antioxidant treatment could open new tailored-therapeutic and prevention strategies still not tested in this disease.

Disclosure

No disclosure

Introduction

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) induce weight loss, and have been associated with an overall decreased risk of esophageal cancer. Obesity is strongly associated with esophageal adenocarcinoma and substantial weight loss may decrease the risk of this malignancy, whereas weight loss does not decrease the risk of esophageal squamous cell carcinoma. We examined the hypotheses that GLP-1RA treatment decreases the risk of esophageal adenocarcinoma.

Aims & Methods

This population-based case-control study included all cases of esophageal adenocarcinoma and esophageal squamous cell carcinoma in adults who had dispensed medication for type 2 diabetes in Denmark (2007-2020), Finland (2011-2018), Iceland (2009-2019), Norway (2007-2019), or Sweden (2007-2020). For each case participant, >10 control participants who had dispensed medication for type 2 diabetes were randomly sampled from the general populations. Data came from well-validated nationwide health-data registries with prospectively collected data. Multivariable logistic regression provided odds ratios (OR) for esophageal adenocarcinoma and esophageal squamous cell carcinoma with 95% confidence intervals (CI), adjusted for sex, age, calendar year, country, comorbidity, obesity, alcohol overconsumption, and tobacco smoking.

Results

This study included 2,909 case participants with esophageal adenocarcinoma, 670 case participants with esophageal squamous cell carcinoma, and 55,408 control participants. The risk of esophageal adenocarcinoma was not decreased in GLP-1RA users compared with non-users (adjusted OR 1.3, 95% CI 1.1-1.5). However, the risk of esophageal squamous cell carcinoma was decreased (adjusted OR 0.5, 95% CI 0.3-0.8).

Conclusion

Standard GLP-1RA treatment in patients with type 2 diabetes might not decrease the risk of esophageal adenocarcinoma. Confounding by indication may have been the most important, or even the sole, contributor to the decreased risk of esophageal squamous cell carcinoma observed, although anticarcinogenic mechanisms of GLP-1RAs other than weight loss cannot be ruled out.

Introduction

The LiverRisk score has been developed as blood-based tool to estimate liver stiffness measurement (LSM) in the general population (i.e., in subjects without known chronic liver disease (CLD), and thus, detect compensated advanced chronic liver disease (cACLD; LSM ≥10kPa) and stratify their risk of liver-related events. Notably, its utility in other settings is unclear as a one-size-fits-all blood-based test. We aimed to evaluate its diagnostic/prognostic performance in patients referred to specialized hepatology outpatient clinics (i.e., tertiary care).

Aims & Methods

Subjects with known/suspected CLD at first LSM (cohort-I, n=5897) or first referral & LSM (cohort-II, n=1558) were retrospectively included. Calibration/agreement of the LiverRisk score with LSM was assessed as well as its diagnostic accuracy for LSM-defined cACLD compared to FIB-4/APRI. Finally, its predictive performance for hepatic decompensation was evaluated.

Results

In cohort-I/II, mean age was 48.3/51.8years, 44.2%/44.7% were female, predominant etiologies were viral hepatitis (51.8%)/MASLD (63.7%), median LSM was 6.9 [5.1-10.9]/ 5.8 [4.5-8.8]kPa, and 1690 (28.7%)/ 322 (20.7%) had cACLD.
Despite a moderate correlation (Pearson’s r: 0.325/0.422), the LiverRisk score systematically underestimated LSM (mean difference according to the Bland-Altman-method: -2.9/-1.8 points≙kPa). Variation of observed differences was considerable (95%CI of agreement: 39.4 and 35.2 points≙kPa), and showed a clear pattern towards larger disagreement at higher values with lower LiverRisk score than LSM.
The diagnostic accuracy of the LiverRisk for cACLD (AUROC: 0.757 [95%CI: 0.744-0.770]/ 0.790 [95%CI: 0.762-0.819]) was comparable to FIB-4 (0.769/0.813) and APRI (0.747/0.765). The cut-off of 10points≙kPa yielded an overall accuracy of 74.2%/81.2%, high specificity (91.9/93.4%), but low negative predictive value (76.6/84.5%) with false-negative results in 20.0%/13.5% in cohort-I/II, respectively.
In cohort-I, 208 (3.5%) patients developed hepatic decompensation (median follow-up: 4.7years). The LiverRisk score showed a reasonable accuracy for predicting hepatic decompensation within 2 years (AUROC: 0.817); however, it was inferior to LSM (0.891, p<0.001) and FIB-4 (0.912, p<0.001). The strata of LiverRisk score (and of LSM/FIB-4) discriminated patient groups of distinct risks for hepatic decompensation.

Conclusion

While being a major step forward for screening subjects without known liver disease in primary care, the LiverRisk score was not superior (vs. FIB-4) for diagnosis of cACLD or (vs. FIB-4/LSM) for prediction of hepatic decompensation in a tertiary care setting, i.e., in cohorts with a higher pre-test probability of cACLD. Notably, FIB-4 even outperformed the LiverRisk score in terms of prognostic utility.