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

Abstract

Hepatopulmonary syndrome (HPS) is a frequent pulmonary complication of end-stage liver disease, characterized by impaired arterial oxygenation induced by intrapulmonary vascular dilatation. Its prevalence ranges from 4% to 47% in patients with cirrhosis due to the different diagnostic criteria applied among different studies. Nitric oxide overproduction and angiogenesis seem to be the hallmarks of a complicated pathogenetic mechanism, leading to intrapulmonary shunting and ventilation-perfusion mismatch. A classification of HPS according to the severity of hypoxemia has been suggested. Contrast-enhanced echocardiography represents the gold standard method for the detection of intrapulmonary vascular dilatations which is required, in combination with an elevated alveolar arterial gradient to set the diagnosis. The only effective treatment which can modify the syndrome's natural history is liver transplantation. Although it is usually asymptomatic, HPS imparts a high risk of pretransplantation mortality, independently of the severity of liver disease, while there is variable data concerning survival rates after liver transplantation. The potential of myocardial involvement in the setting of HPS has also gained increasing interest in recent research. The aim of this review is to critically approach the existing literature of HPS and emphasize unclear points that remain to be unraveled by future research.

Keywords: Contrast echocardiography; Hepatopulmonary syndrome; Liver cirrhosis; Liver transplantation; Portal hypertension.

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.