LAUSR

Hepatopulmonary syndrome (HPS) is classified as a pulmonary vascular disorder that occurs in liver disease and/or portal hypertension and is characterized by intrapulmonary vascular dilatation with arterial deoxygenation. Nitric oxide (NO) is a key factor for systemic and pulmonary vasodilatation and plays a certain role in the hyperdynamic circulatory state in the patients. It is the consequence of abnormal angiogenesis of the pulmonary microcirculation [1]; distal vessels are involved in remodeling, including dilated precapillary and capillary vessels and precapillary arteriovenous communications [2]. HPS is detected in acute/ chronic liver diseases irrespective of the presence/absence of portal hypertension; the prevalence is approximately 10% in chronic viral hepatitis with or without cirrhosis, 18% in orthotopic liver transplantation candidates and as high as 28% in Budd-Chiari syndrome [3, 4]. Cirrhosis is the common liver disease leading to HPS. A prospective study in 111 cirrhotic patients reported that the mortality of patients with HPS was significantly higher (median survival, 10.6 months) than the mortality of patients without HPS (40.8 months, p < 0.05), even after adjusting for the severity of liver disease (2.9 months in patients with HPS [n = 15] and 14.7 months without HPS [n = 35, p < 0.05] in Child–Pugh class C) [5]. The presence of HPS was also an independent predictor of survival by multivariate analysis, and mortality correlated with the severity of HPS. Therefore, the presence of HPS seems to be an independent and significant factor for the prognosis of cirrhotic patients. The development of portosystemic collaterals, reduced liver function typified by the reduction of the intrahepatic phagocytosis and the occurrence of bacterial translocation in cirrhosis, provide inflammatory and angiogenic cytokines, circulating bacteria or bacterial endotoxins to enter the pulmonary circulation, damage the pulmonary endothelium and induce extensive recruitment of pulmonary intravascular macrophages [6, 7]. Recent basic studies suggest that bacterial translocation and/or proinflammatory cytokines such as tumor necrosis factor-a, interleukin-1 (IL-1) and IL-8, which are upregulated in the lung and pulmonary intravascular macrophages, are involved in the pathogenesis of HPS [8–10]. Acute-on-chronic liver failure (ACLF) is considered a distinct clinical syndrome that is demonstrated among patients with acutely decompensated chronic liver disease and/or cirrhosis. ACLF is characterized by an intense systemic inflammatory response, singleor multiple organ system failures, and a high 28-day mortality rate [11], although detailed definitions differ according to the different international criteria, Europe, North America, Asian Pacific region, and China [12]. The poor prognosis of ACLF is generally recognized; transplantation-free mortality rates were 32.8% at 28 days and 51.2% at 90 days in patients with ACLF and 1.8% at 28 days and 9.8% at 90 days in those without ACLF [13]. With the increased prevalence of nonalcoholic fatty liver disease (NAFLD) worldwide, a recent study from the United States based on the survey between 2005 and 2017 has shown the waitlist registrants for NAFLD-ACLF rose by 331.6% from 134 to 574 candidates (p < 0.001), representing the largest percentage increase in the study population [14]. They suggested that patients with NAFLD-ACLF will likely have the highest risk of waitlist mortality. Against this background, Ki et al. conducted a longitudinal prospective observational study in 142 patients with cirrhosis (median follow-up period, 28 months), all of whom underwent saline-agitated contrast echocardiography for the diagnosis of HPS in South Korea from 2014 to December 2019 [15]. In the basis of diagnosis, unfortunately, the definition/criteria of ACLF and HPS are not clearly described in the manuscript. As for the former, the authors might have used the Asian Pacific Association for the Study of the Liver (APASL) definition as a member of Asian countries, acute hepatic insult manifesting as jaundice (total bilirubin levels of 5 mg/dl or more) and coagulopathy (international normalized ratio > − 1.5, or prothrombin activity < 40%) * Hitoshi Maruyama [email protected]