Association between gut-derived endotoxins and porto-sinusoidal vascular disorder with portal hypertension

Background: Porto-sinusoidal vascular disorder (PSVD) is characterised by lesions involving portal veins and sinusoids in absence of cirrhosis with an unclear pathophysiology. However, its association with immunodeficiency, bowel disorders and abdominal bacterial infections supports the role of altered intestinal permeability and gut-derived endotoxins. The study aimed at assessing the association between serological markers of increased intestinal permeability, pro-aggregating/procoagulant state and liver injury in PSVD and portal hypertension. Methods: Thirty-three patients with biopsy-proven PSVD and portal hypertension and 33 healthy subjects were submitted to a venous blood sampling for the measurement of zonulin and lipopolysaccharides (LPS) as markers of intestinal permeability, of s-Glycoprotein VI, sP-selectin, ADAMTS13 and von Willebrand factor (vWF), as markers of platelet aggregation and microvascular inflammation, factor VIII and F1 + 2 as markers of hypercoagulability. In 17 PSVD patients, histomorphological and immunohistochemical study on liver biopsies was performed. Results: Compared with controls, PSVD patients had higher levels of LPS, zonulin, vWF, factor VIII and sP-selectin, F1 + 2. ADAMTS13 was reduced. Serum LPS correlated with zonulin, sP-selectin, FVIII and vWF. At histological analysis, PSVD specimens had increased LPS localisation, toll-like receptor-4(TLR4)-positive macrophages and platelet number compared with samples from healthy liver donors. TLR4+ macrophage number correlated with portal inflammation and fibrosis. Sinusoid dilation and capillarisation were observed. PSVD biopsies showed signs of biliary damage and reduced ductular reaction without alteration in Sox9+ cell population. Conclusions: PSVD patients display an altered intestinal permeability and endotoxemia correlated to a pro-aggregating/procoagulant state; histologically, PSVD was associated with increased TLR4+ cell involvement and platelet clumps within sinusoids. Our study suggests that LPS-TLR4 pathway could contribute to the pathophysiological basis of PSVD with portal hypertension.