Hepatopulmonary syndrome

Abstract

Hepatopulmonary syndrome (HPS) is a pulmonary vascular complication of liver disease, which adversely affects prognosis. The disease is characterised by intrapulmonary vascular dilatations and shunts, resulting in impaired gas exchange. A complex interaction between the liver, the gut and the lungs, predominately impacting pulmonary endothelial cells, immune cells and respiratory epithelial cells, is responsible for the development of typical pulmonary alterations seen in HPS. Liver transplantation is the only therapeutic option and generally reverses HPS. Since the implementation of the model for end-stage liver disease (MELD) standard exception policy, outcomes in patients with HPS have been significantly better than they were in the pre-MELD era. This review summarises current knowledge and highlights what's new regarding the diagnosis and management of HPS, and our understanding of pathogenesis based on experimental models and translational studies.

Keywords: ABG, arterial blood gas; AT2, alveolar type II; AV, arteriovenous; CBDL, common bile duct ligation; ET-1, endothelin-1; ETB, endothelin receptor B; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; HPS, hepatopulmonary syndrome; IPVDs, intrapulmonary vascular dilatations; LT, liver transplantation; MELD exceptions; NO, nitric oxide; P(A-a)O2, alveolar-arterial oxygenation gradient; PDGF, platelet-derived growth factor; PIGF, placental growth factor; PVL, portal vein ligation; PaO2, partial pressure of arterial oxygen; SE, standard exception; SP, surfactant protein; SaO2, oxygen saturation; TAA, thio-acetamide; TNFα, tumour necrosis factor alpha; Tc-MAA, 99mTechnetium-labeled macroaggregated albumin; UNOS, United Network for Organ Sharing; V/Q, ventilation-perfusion; VCAM1, vascular cellular adhesion molecule 1; VEGF, vascular endothelial growth factor; cirrhosis; portal hypertension; vWF, von Willebrand factor.

Fig. 1

Diagnostic criteria for HPS. i) Liver disease and/or portal hypertension. ii) Evidence of IPVDs and/or shunting. Gold standard is contrast-enhanced echocardiography. ‘Delayed’ presence of microbubbles in the left heart after intravenous injection (3 or more cardiac cycles after being seen in the right heart) indicates IPVDs or shunts. iii) P(A-a)O₂ gradient ≥15 mmHg (or >20 in case of ≥65 years of age), as determined by ABG analysis. ABG, arterial blood gas; HPS, hepatopulmonary syndrome; IPVDs, intrapulmonary vascular dilatations; P(A-a)O₂, alveolar-arterial oxygenation gradient.

Fig. 2

Screening and diagnosis of HPS. Proper screening and diagnosis of HPS relies on performing contrast-enhanced echocardiography and arterial blood gas analysis. Biomarkers could facilitate the identification of HPS in patients with cirrhosis, but additional studies and validation in larger cohorts is needed. HPS, hepatopulmonary syndrome; IPVDs, intrapulmonary vascular dilatations; P(A-a)O₂, alveolar-arterial oxygenation gradient.

Fig. 3

Pathophysiology and pathogenesis of HPS. A complex interaction between the liver, the gut and the lungs, predominately impacting pulmonary endothelial cells, immune cells and respiratory epithelial cells, is responsible for the development of IPVDs and intrapulmonary shunting in HPS. These phenomena result in V/Q mismatch, diffusion restriction and right-to-left shunting, responsible for impaired gas exchange and hypoxemia. Bacterial translocation with pulmonary intravascular recruitment of immune cells, pulmonary endothelial dysfunction, angiogenesis, and AT2 cell dysfunction represent the most important underlying mechanisms and are considered potential therapeutic targets. AT2, alveolar type II; AV, arteriovenous; CO, carbon monoxide; HPS, hepatopulmonary syndrome; NO, nitric oxide; V/Q, ventilation-perfusion.

Fig. 4

Natural history of HPS. HPS is frequently detected by screening; most patients are asymptomatic or only experience dyspnea on exertion. ABG reveals a widened P(A-a) O₂ gradient. Hypoxemia is usually progressive over years. Untreated HPS carries poor prognosis. LT represents the only curable treatment option, and has led to significant survival improvements for affected patients over recent years. ABG, arterial blood gas; HPS, hepatopulmonary syndrome; LT, liver transplantation; P(A-a)O₂, alveolar-arterial oxygenation gradient; SE, standard exception.