Hepatopulmonary syndrome: update on pathogenesis and clinical features

Abstract

Hepatopulmonary syndrome (HPS) is a serious vascular complication of liver disease that occurs in 5-32% of patients with cirrhosis. The presence of HPS markedly increases mortality. No effective medical therapies are currently available and liver transplantation is the only established treatment option for HPS. The definition and diagnosis of HPS are established by the presence of a triad of liver disease with intrapulmonary vascular dilation that causes abnormal arterial gas exchange. Experimental biliary cirrhosis induced by common bile duct ligation in the rat reproduces the pulmonary vascular and gas exchange abnormalities of human HPS and serves as a pertinent animal model. Pulmonary microvascular dilation and angiogenesis are two central pathogenic features that drive abnormal pulmonary gas exchange in experimental HPS, and thus might underlie HPS in humans. Defining the mechanisms involved in the microvascular alterations of HPS has the potential to lead to effective medical therapies. This Review focuses on the current understanding of the pathogenesis, clinical features and management of HPS.

Figure 1

Working model of pathogenic mechanisms in experimental HPS. The key pathophysiological features of experimental HPS induced by CBDL cirrhosis are pulmonary microvascular alterations, including vasodilation, intravascular monocyte accumulation and angiogenesis. Pulmonary vasodilation is triggered by excessive NO production through ET-1/ET_B receptor-driven eNOS activation and iNOS induction in intravascular monocytes, as well as the altered CO production (caused by altered levels of HMOX1) in monocytes. Moreover, monocytes adhered to the pulmonary vasculature produce growth factors such as VEGFA, which contribute to the development of angiogenesis by activating angiogenic signalling pathways including Akt and ERK in endothelial cells. Abbreviations: Akt, protein kinase B; CBDL, common bile duct ligation; CO, carbon monoxide; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal-regulated protein kinase; ET-1, endothelin-1; ET_B receptor, endothelin B receptor; HPS, hepatopulmonary syndrome; HMOX1, heme oxygenase 1 (also known as HO1); iNOS, inducible nitric oxide synthase; NO, nitric oxide; TNF, tumour necrosis factor; VEGFA, vascular endothelial growth factor A; VEGFR, vascular endothelial growth factor receptor.