RESUMEN
RATIONALE: Hepatopulmonary syndrome (HPS) is a severe complication of liver diseases characterized by abnormal dilatation of pulmonary vessels, resulting in impaired oxygenation. Recent research highlights the pivotal role of liver-produced bone morphogenetic protein (BMP)-9 in maintaining pulmonary vascular integrity. OBJECTIVES: This study aimed to investigate the involvement of BMP-9 in human and experimental HPS. METHODS: Circulating BMP-9 levels were measured in 63 healthy controls and 203 cirrhotic patients, with or without HPS. Two animal models of portal hypertension were employed: common bile duct ligation (CBDL) with cirrhosis and long-term partial portal vein ligation (PPVL) without cirrhosis. Additionally, the therapeutic effect of low-dose BMP activator FK506 was investigated, and the pulmonary vascular phenotype of BMP-9 knockout rats was analyzed. MEASUREMENTS AND MAIN RESULTS: Patients with HPS related to compensated cirrhosis demonstrated lower levels of circulating BMP-9 compared to patients without HPS. Severe cirrhosis patients exhibited consistently low levels of BMP-9. In animal models, HPS characteristics, including intrapulmonary vascular dilations (IPVDs) and alveolo-arterial gradient enlargement, were observed. HPS development in both rat models correlated with reduced intrahepatic BMP-9 expression, decreased circulating BMP-9 level and activity, and impaired pulmonary BMP-9 endothelial pathway. Daily treatment with FK506 for 2-weeks restored BMP pathway in the lungs, alleviating IPVDs, and improving gas exchange impairment. Furthermore, BMP-9 knockout rats displayed a pulmonary HPS phenotype, supporting its role in disease progression. CONCLUSION: The study findings suggest that portal hypertension-induced loss of BMP-9 signaling contributes to HPS development.
RESUMEN
BACKGROUND: Liver transplant patients who develop hyperlactatemia are at increased risk of postoperative morbidity and short-term mortality, but there are few data on longer-term outcomes. We therefore investigated if arterial lactate concentration obtained immediately after surgery, at the time of admission to the intensive care unit (ICU), was associated with 1-year mortality. METHODS: In this retrospective cohort study, all patients who underwent liver transplant surgery from a deceased donor between September 2013 and December 2019 were screened for inclusion. Patients who underwent combined transplantation surgery and those with a history of previous liver transplantation (ie, redo surgery) were not included. Logistic regression modeling included univariate and multivariate analyses. Receiver operating characteristic curves and areas under the curves were calculated. Lactate thresholds and association with outcome were analyzed for specificity, sensitivity, and Youden's index. RESULTS: Of 226 patients included, 18.4% died within 1 year of liver transplantation. Immediate postoperative lactate concentration was independently associated with 1-year mortality with an adjusted odds ratio of 1.35 (95% CI 1.16-1.59; P < .001) per mmol/L increase in lactate and an area under the curve of 0.80 (95% CI 0.72-0.87; P < .001). A lactate concentration of 2.25 mmol/L (cutoff determined using Youden's index) was associated with increased 1-year mortality with a sensitivity of 0.71 and a specificity of 0.72. CONCLUSIONS: Increased arterial lactate concentration on admission to the intensive care unit immediately after orthotopic liver transplantation is independently associated with increased 1-year mortality.