Intestinal barrier dysfunction assessed by confocal laser endomicroscopy correlates with cirrhosis severity and clinical outcome☆

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Background & Aims Intestinal barrier dysfunction drives complications in advanced chronic liver disease (ACLD). Confocal laser endomicroscopy (CLE) enables direct visualization of transepithelial fluorescein leakage during endoscopy. This study evaluated the link between CLE-assessed intestinal permeability and disease severity in ACLD. Methods CLE was performed in two independent cohorts after intravenous fluorescein administration in the small intestine: (1) Bern cohort (n=4 healthy controls, n=16 ACLD) and (2) Vienna cohort (n=48 ACLD). Image analysis included established CLE scores, and novel quantitative assessments measuring fluorescence intensity in three compartments ("3-compartment-method"; lumen–epithelium–lamina propria) and along the epithelium ("3-line-method"; base–middle–apex). CLE-derived metrics were correlated with disease stage and biomarkers. In the Vienna cohort, correlation with portal hypertension (HVPG) and liver-related events (LRE: decompensation, ACLF, death) was assessed. Results Transepithelial fluorescein permeation into the gut lumen was absent in healthy controls but frequent in ACLD, and increased with disease severity (Vienna cohort: compensated vs. first decompensation vs. further decompensation: 24%, 57%, and 71%, p=0.019). The 3-line and 3-compartment methods robustly distinguished healthy controls from cirrhosis (3-line apex/base ratio: 0.42 ±0.12 vs. ACLD 0.83 ±0.18, p=0.001), and exhibited lowest inter-observer variability. In both cohorts, quantitative permeability measures - especially epithelial 3-line apex/base ratio and 3-line-slopes (all p<0.05) - increased across Child-Turcotte-Pugh stages, and correlated with HVPG (apex/base-ratio: r=0.575, p<0.001) and liver function parameters (e.g. albumin: r=-0.553, p<0.001). CLE-based barrier dysfunction was linked to higher LRE incidence during follow-up (Cox regression; apex/base ratio: HR 10.6, 95% CI 1.71–66.0, p=0.011). Conclusion CLE identifies high prevalence of intestinal permeability in ACLD, correlating with disease stage and adverse outcomes. The novel 3-line epithelial analysis demonstrated strong associations with portal hypertension and biomarkers reflecting ACLD severity. Impact and implications Intestinal barrier dysfunction is a key driver of complications in advanced chronic liver disease. Using confocal laser endomicroscopy (CLE) during endoscopy, the present study shows that transepithelial fluorescein leakage can be visualized and quantified, and aligns with cirrhosis stage, portal hypertension, and liver-related outcomes. These findings are relevant for hepatologists and translational researchers, as this technique might be used to identify patients with intestinal barrier dysfunction. Because the present analyses are exploratory and derive from two cohorts with limited sample size and requirement for manual image analysis, larger prospective studies and feasibility of (semi-)automated quantification are required before CLE-based permeability assessment can be applied more broadly. Clinical trial number NCT03267615