Introduction
Dysfunctional and leaky gut barrier are characteristics of cirrhosis and associated with disease progression and mortality. Utility of biomarkers, indicating the presence and extent of intestinal barrier dysfunction, remains a controversial issue in the prognosis and risk stratification of decompensated cirrhosis. Villin-1 (VIL1) is an actin-bundling protein, present in the intestinal, renal and biliary brush border. VIL1 is downregulated in response to chronic injury and diverse cellular stressors, including the microbiome, while during acute stress it is redistributed from the brush border to the basolateral membrane, which facilitates its release into the blood.
Aims & Methods
We investigated clinical significance of serum VIL1 levels in patients with cirrhosis and acute decompensation (AD).Patients (n = 86) and healthy controls (HC; n = 50) from the MICROB-PREDICT cohort were tested for serum VIL1 by ELISA. Four patient severity sub-groups were defined according to the PREDICT study (stable AD (SDC), unstable AD (UDC), pre-ACLF and ACLF [acute-on-chronic liver failure]). VIL1 immunohistochemistry (IHC) evaluation of duodenum biopsy was performed in a sub-cohort of the patients (n = 13) and controls (n = 11).
Results
Serum VIL1 levels were decreased in SDC patients (median [IQR]: 6.5 [4.9-10.4] vs 12 [8.4-14.9] ng/mL, p < 0.001) compared to controls and increased in more severe disease. This difference was confirmed in duodenum tissue by IHC. Significantly higher serum VIL1 levels were detected in pre-ACLF patients compared to those who did not develop ACLF (10.7 [7.8-22.9] vs 6.9 [5.0-10.5] ng/mL, p = 0.004), while in ACLF survivors decreased VIL1 levels were observed on day-7 compared to day-0 (9.8 [7.3-14.6] vs 12.7 [9.7-18.1] ng/mL, p = 0.010). High serum VIL1 levels (≥16.17 ng/mL) predicted 90-day mortality (AUROC:0.73, 95%CI: 0.563-0.888, p = 0.013) and in combination with high (≥ 50) CLIF-C AD score the prediction accuracy was excellent (both is high: 75%; all other together: 8% mortality, LogRank p < 0.001). High serum VIL1 level was able to predict mortality both in the presence (20% vs 62% LogRank p = 0.030) and absence (14% vs 40% LogRank p = 0.008) of renal failure.
Conclusion
Besides the six organ failures included in CLIF-SOFA, patients with cirrhosis and AD may also develop intestinal failure, as an additional organ failure. Serum VIL1 level could reliably indicate this organ failure and made the mortality risk stratification performed by CLIF-C OF score more accurate.
Disclosure
The MICROB-PREDICT project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 825694