In patients with cirrhosis and portal hypertension, studies have demonstrated a significant increase in abdominal lymph production and lymph flow in thoracic duct ( Vollmar et al., 1997). Intestinal inflammation is correlated with extensive intestinal lymphangiogenesis, and specific loss of intestinal lymphatics results in severe gut inflammation, sepsis, and complete short-term lethality, highlighting the crucial role of intestinal lymphatics in inflammation ( Jang et al., 2013). The intestinal lymphatic system has been associated with pathologies, including inflammatory bowel disease and obesity ( D’alessio et al., 2014 Cao et al., 2021).

The intestinal lymphatic capillaries (lacteals) and associated collecting vessels in the mesentery form the drainpipe that clears interstitial fluid, inflammatory cells and molecules, and microbial debris from the abdominal viscera. It plays a major role in dietary fat uptake and transport, viscera fluid balance, and gut immunosurveillance ( Bernier-Latmani and Petrova, 2017). The intestinal lymphatic vasculature comprises the longest-studied lymphatic vessel (LVs) bed. PDPN score correlates with enhanced gut and systemic inflammation and also associates with 3-month mortality in cirrhosis. Collectively, dilated LVs with high PDPN expression in D2-biopsies is a characteristic feature of patients with decompensated cirrhosis. 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. In Cox regression, the PDPN score was a significant and independent 3-month-mortality predictor in patients (HR: 5.61 1.08-29.109 p = 0.04). 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 TJP1 expression (r = -0.46, p < 0.05 each). The mean PDPN score in decompensated cirrhosis patients (6.91 ± 1.26, p < 0.0001) was significantly increased as compared to those with compensated (3.25 ± 1.60). Gene expression of LV markers, PDPN (8-fold), and LYVE1 (3-fold) was enhanced in D2-biopsies of cirrhosis patients compared to control ( p < 0.0001). Gut permeability and inflammation as assessed by quantifying gene expression of TJP1, OCLN, TNF-α, and IL-6 in D2-biopsies. Gut and systemic inflammation were estimated by quantifying duodenal CD3 + intraepithelial lymphocytes (IELs), CD68 + macrophages, and serum TNF-α and IL-6 levels, respectively. 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. A prospective, single-center cohort study was performed in liver cirrhosis patients ( n = 31) and matched healthy controls ( n = 9). 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. 3Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, Indiaĭilated and dysfunctional gut lymphatic vessels (LVs) have been reported in experimental cirrhosis.2Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.1Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.

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