AUTHOR=Juneja Pinky , Sharma Aarti , Shasthry S. M. , Kumar Guresh , Tripathi Dinesh M. , Rajan V. , Rastogi Archana , Sarin Shiv K. , Kaur Savneet 

TITLE=Podoplanin-positive dilated lymphatic vessels in duodenum associates with three-month mortality in patients with cirrhosis

JOURNAL=Frontiers in Physiology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2023.1045983

DOI=10.3389/fphys.2023.1045983

ISSN=1664-042X

ABSTRACT=<p>Dilated and dysfunctional gut lymphatic vessels (LVs) have been reported in experimental cirrhosis. Here, we studied LVs in duodenal (D2)-biopsies of liver cirrhosis patients and investigated the prognostic role of a LV marker, podoplanin (PDPN), in predicting the mortality of patients with cirrhosis. A prospective, single-center cohort study was performed in liver cirrhosis patients (<italic>n</italic> = 31) and matched healthy controls (<italic>n</italic> = 9). D2-biopsies were obtained during endoscopy procedure, immunostained with PDPN, and scored based on 1) intensity and 2) density of positively-stained LVs per high power field. Gut and systemic inflammation were estimated by quantifying duodenal CD3<sup>+</sup> intraepithelial lymphocytes (IELs), CD68<sup>+</sup> macrophages, and serum TNF-α and IL-6 levels, respectively. Gut permeability and inflammation as assessed by quantifying gene expression of <italic>TJP1</italic>, <italic>OCLN, TNF-α,</italic> and <italic>IL-6</italic> in D2-biopsies. Gene expression of LV markers, <italic>PDPN</italic> (8-fold), and <italic>LYVE1</italic> (3-fold) was enhanced in D2-biopsies of cirrhosis patients compared to control (<italic>p</italic> &lt; 0.0001). The mean PDPN score in decompensated cirrhosis patients (6.91 ± 1.26, <italic>p</italic> &lt; 0.0001) was significantly increased as compared to those with compensated (3.25 ± 1.60). PDPN score positively and significantly correlated with the number of IELs (r = 0.33), serum TNF-α (r = 0.35), and IL-6 (r = 0.48) levels, while inversely correlated with <italic>TJP1</italic> expression (r = -0.46, <italic>p</italic> &lt; 0.05 each). In Cox regression, the PDPN score was a significant and independent 3-month-mortality predictor in patients (HR: 5.61; 1.08-29.109; <italic>p</italic> = 0.04). The area under the curve for the PDPN score was 84.2, and cutoff value for predicting mortality was ≥6.5 with 100% sensitivity and 75% specificity. Collectively, dilated LVs with high PDPN expression in D2-biopsies is a characteristic feature of patients with decompensated cirrhosis. PDPN score correlates with enhanced gut and systemic inflammation and also associates with 3-month mortality in cirrhosis.</p>