Hepatopulmonary Syndrome: Update on Recent Advances in Pathophysiology, Investigation, and Treatment

Josephine A Grace; Peter W Angus

Disclosures

J Gastroenterol Hepatol. 2013;28(2):213-219. 

In This Article

Abstract and Introduction

Abstract

Hepatopulmonary syndrome (HPS) is an important cause of dyspnea and hypoxia in the setting of liver disease, occurring in 10–30% of patients with cirrhosis. It is due to vasodilation and angiogenesis in the pulmonary vascular bed, which leads to ventilation-perfusion mismatching, diffusion limitation to oxygen exchange, and arteriovenous shunting. There is evidence, primarily from animal studies, that vasodilation is mediated by a number of endogenous vasoactive molecules, including endothelin-1 and nitric oxide (NO). In experimental HPS, liver injury stimulates release of endothelin-1 and results in increased expression of ETB receptors on pulmonary endothelial cells, leading to upregulation of endothelial NO synthase (eNOS) and subsequent increased production of NO, which causes vasodilation. In addition, increased phagocytosis of bacterial endotoxin in the lung not only promotes stimulation of inducible NO synthase, which increases NO production, but also contributes to intrapulmonary accumulation of monocytes, which may stimulate angiogenesis via vascular endothelial growth factor pathway. Despite these insights into the pathogenesis of experimental HPS, there is no established medical therapy, and liver transplantation remains the main treatment for symptomatic HPS, although selected patients may benefit from other surgical or radiological interventions. In this review, we focus on recent advances in our understanding of the pathophysiology of HPS, and discuss current approaches to the investigation and treatment of this condition.

Introduction

Two intriguing and incompletely understood disorders of the pulmonary vasculature can cause pulmonary dysfunction in cirrhotic patients. The more common is hepatopulmonary syndrome (HPS), in which the primary pathological process is abnormal pulmonary vasodilation. This condition represents one manifestation of generalized circulatory dysfunction in portal hypertension, which is characterized by vascular dilatation and development of a hyperdynamic circulation. The other, but far less common, pulmonary vascular disorder associated with cirrhosis is portopulmonary hypertension. Here, the pulmonary circulatory abnormality is vasoconstriction, and there is fibro-obliteration of the vascular bed, the opposite from the changes that occur in HPS. Rarely, patients can have features of both disorders.[1]

HPS is defined as the presence of the triad of an arterial oxygenation defect, intrapulmonary vasodilation, and the presence of liver disease.[2] It is usually diagnosed in patients with cirrhosis, but neither cirrhosis nor portal hypertension is a prerequisite for the diagnosis, as it has been reported in chronic non-cirrhotic hepatitis,[3] non-cirrhotic portal hypertension,[4,5] Budd–Chiari syndrome,[6] and even in acute liver diseases, such as fulminant hepatitis A[7] and ischemic hepatitis.[8] Estimates of the prevalence of HPS are complicated by a lack of consensus in the past regarding the diagnostic criteria. In particular, the degree of gas exchange abnormality required to make the diagnosis is variable, so that even within the same group of cirrhotic patients in one study, the apparent prevalence varied from 19% to 32%.[9] Most studies have been conducted in patients with advanced liver disease undergoing assessment for liver transplantation, in whom the prevalence ranges from 16% to 33%.[10–14] Limited data suggest that a slightly lower prevalence of 10–17% exists in the overall cirrhotic population.[15,16]

Thus, HPS represents a relatively common and important cause of pulmonary disease in patients with cirrhosis. This review will focus on recent advances in our understanding of the pathophysiology of HPS, and discuss appropriate investigation, prognosis, and treatment of patients with HPS.

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