Review article: Update on current and emergent data on hepatopulmonary syndrome

Figure 1 Schematic overview of the main pathways of the pathogenesis of hepatopulmonary syndrome. Liver cirrhosis and portal hypertension lead to endothelin-1 (ET-1) secretion. The binding of ET-1 to its receptor, activates pulmonary endothelial nitric oxide synthase (eNOS), leading to excessive production of nitric oxide (NO), a natural vasodilator. Bacterial translocation and the subsequent pulmonary macrophage accumulation result in the production of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), which contribute in NO-mediated vasodilatation through inducible nitric oxide synthase (iNOS)-enhanced expression. Carbon monoxide constitutes another pulmonary vasodilator produced by macrophage-induced heme oxygenase-1 (HO-1) increased expression. Pulmonary macrophage accumulation and TNF-α-increased circulation trigger vascular endothelial growth factor (VEGF) pathways, concluding in VEGF-mediated pulmonary angiogenesis. Mixed venous blood passes rapidly, due to hyperdynamic circulation observed in liver cirrhosis, through the dilated capillaries without completing gas exchange. An oxygen (O₂) diffusion limitation occurs, as O₂ molecules need to cross a longer distance to reach the center of dilated vasculature. As a result, there is an impairment of arterial oxygenation due to ventilation perfusion mismatch, also boosted by direct right-to-left shunt through arteriovenous communications.