Hepatopulmonary Syndrome Patients Research Articles

Spleen derived monocytes regulate pulmonary vascular permeability in Hepatopulmonary syndrome through the OSM-FGF/FGFR1 signaling

Hepatopulmonary syndrome (HPS) is a serious pulmonary complication in the advanced stage of liver disease. The occurrence of pulmonary edema in HPS patients is life-threatening. Increased pulmonary vascular permeability is an important mechanism leading to pulmonary edema, and endothelial glycocalyx (EG) is a barrier that maintains stable vascular permeability. However, in HPS, whether the pulmonary vascular EG changes and its regulatory mechanism are still unclear. Spleen derived monocytes are involved in the pathogenesis of HPS. However, whether they regulate the pulmonary vascular permeability in HPS patients or rats and what is the mechanism is still unclear. Healthy volunteers and HPS patients with splenectomy or not were enrolled in this study. We found that the respiration of HPS patients was significantly improved in response to splenectomy, while the EG degradation and pulmonary edema were aggravated. In addition, HPS patients expressed higher levels of oncostatin M (OSM) and fibroblast growth factor (FGF). Subsequently, the co-culture system of monocytes and human umbilical vein endothelial cells (HUVECs) was constructed. It was found that monocytes secreted OSM and activated the FGF/FGFR1 signaling pathway in HUVECs. Then, an HPS rat model was constructed by common bile duct ligation (CBDL) for in vivo verification. HPS rats were intravenously injected with OSM recombinant protein and/or TNF-α into the rats via tail vein 30 min before CBDL. The results showed that the respiration of HPS rats was improved after splenectomy, while the degradation of EG in pulmonary vessels and vascular permeability were increased, and pulmonary edema was aggravated. Moreover, the expression of OSM and FGF was upregulated in HPS rats, while both were downregulated after splenectomy. Intravenous injection of exogenous OSM eliminated the effect of splenectomy on FGF and improved EG degradation. It can be seen that during HPS, spleen-derived monocytes secrete OSM to promote pulmonary vascular EG remodeling by activating the FGF/FGFR1 pathway, thereby maintaining stable vascular permeability, and diminishing pulmonary edema. This study provides a promising therapeutic target for the treatment of HPS.

Serum Soluble Vascular Endothelial Growth Factor Receptor 1 as a Potential Biomarker of Hepatopulmonary Syndrome.

The results of basic research implicate the vascular endothelial growth factor (VEGF) family as a potential target of hepatopulmonary syndrome (HPS). However, the negative results of anti-angiogenetic therapy in clinical studies have highlighted the need for markers for HPS. Therefore, we aimed to determine whether VEGF family members and their receptors can be potential biomarkers for HPS through clinical and experimental studies. Clinically, patients with chronic liver disease from two medical centers were enrolled and examined for HPS. Patients were divided into HPS, intrapulmonary vascular dilation [positive contrast-enhanced echocardiography (CEE) and normal oxygenation] and CEE-negative groups. Baseline information and perioperative clinical data were compared between HPS and non-HPS patients. Serum levels of VEGF family members and their receptors were measured. In parallel, HPS rats were established by common bile duct ligation. Liver, lung and serum samples were collected for the evaluation of pathophysiologic changes, as well as the expression levels of the above factors. In HPS rats, all VEGF family members and their receptors underwent significant changes; however, only soluble VEGFR1 (sFlt-1) and the sFlt-1/ placental growth factor (PLGF) ratio were changed in almost the same manner as those in HPS patients. Furthermore, through feature selection and internal and external validation, sFlt-1 and the sFlt-1/PLGF ratio were identified as the most important variables to distinguish HPS from non-HPS patients. Our results from animal and human studies indicate that sFlt-1 and the sFlt-1/PLGF ratio in serum are potential markers for HPS.

Vascular Extracellular Vesicles Indicate Severe Hepatopulmonary Syndrome in Cirrhosis

Hepatopulmonary syndrome (HPS) is a pulmonary vasculature complication in the setting of liver disease that is characterized by pathological vasodilation resulting in arterial oxygenation defects. We investigated the role of extracellular vesicles (EV) in cirrhosis patients with HPS, as well as the functional effect of EV administration in a common bile duct ligation (CBDL) HPS mouse model. A total of 113 cirrhosis patients were studied: 42 (Gr. A) with HPS and 71 (Gr. B) without HPS, as well as 22 healthy controls. Plasma levels of EV associated with endothelial cells, epithelial cells, and hepatocytes were measured. The cytokine cargoes were estimated using ELISA. The effect of EV administered intranasally in the CBDL mouse model was investigated for its functional effect in vascular remodeling and inflammation. We found endothelial cells (EC) associated EV (EC-EV) were elevated in cirrhosis patients with and without HPS (p < 0.001) than controls. EC-EV levels were higher in HPS patients (p = 0.004) than in those without HPS. The epithelial cell EVs were significantly high in cirrhosis patients than controls (p < 0.001) but no changes found in patients with HPS than without. There was a progressive increase in EC-EV levels from mild to severe intrapulmonary shunting in HPS patients (p = 0.02 mild vs. severe), and we were able to predict severe HPS with an AUROC of 0.85; p < 0.001. An inverse correlation of EC-EVs was found with hemoglobin (r = -0.24; p = 0.031) and PaO2 (r = 0.690; p = 0.01) and a direct correlation with MELD (r = 0.32; p = 0.014). Further, both TNF-α (p = 0.001) and IL-1β (p = 0.021) as cargo levels were significantly elevated inside the EVs of HPS patients than without HPS. Interestingly, upon administration of intranasal EVs, there was a significant decrease in Evans blue accumulation and lung wet-dry ratio (p = 0.042; 0.038). A significant reduction was also noticed in inflammation and cholestasis. High levels of plasma EC-EV levels were found in patients with HPS with elevated pro-inflammatory cytokine cargoes. EC-EVs were indicative of severe HPS condition. In the CBDL HPS model, we were able to prove the beneficial effects of improving vascular tone, inflammation, and liver pathogenesis.

ICU and Hospital Outcomes in Patients with Hepatopulmonary Syndrome Undergoing Liver Transplantation.

There are limited data regarding hospital and intensive care unit (ICU) outcomes in patients with hepatopulmonary syndrome (HPS) following liver transplantation (LT). Data were retrospectively collected from consecutive HPS adult patients who underwent LT and were immediately admitted to the ICU at three transplant centers with shared management protocols, from 2002 to 2018. Demographic, clinical, surgical, laboratory, and outcome data were extracted. We identified 137 patients (74 male, 54%), with a median age at LT of 58years (IQR: 52-63). One hundred and 31 (95.6%) patients were admitted to the ICU on invasive mechanical ventilation (MV). The median time on invasive MV in the ICU was 12hours (IQR: 5-28) and 97 patients (74%) were extubated within 24hours of ICU admission. The median highest positive end expiratory pressure and fraction of inspired oxygen (FiO2) were 7 (IQR: 5-8) and 0.6 (IQR: 0.5-0.7), respectively. 7 patients (5%) developed severe post-transplant hypoxemia. Of all patients, 42 (30.4%) required vasopressors and the median ICU and hospital length of stay (LOS) were 3 (IQR: 1-5) and 10 (IQR: 7-20) days, respectively. The in-hospital mortality rate was 3.6% (5/137). HPS severity was not associated with hospital mortality. Most HPS patients have short durations of MV, ICU, and hospital LOS post-LT. HPS severity does not impact hospital mortality.

Unmasking Hypoxia in Cirrhosis Patients: Six-Minute Walk Test as a Screening Tool for Hepatopulmonary Syndrome.

Background:Hepatopulmonary syndrome (HPS) is one of the complications of advanced cirrhosis which has a serious impact on prognosis of patient. Finding arterial deoxygenation early and initiating higher-level treatment is one of the most critical strategies in the therapy of HPS. In this study, we aimed to assess the utility of six-minute walk test (6MWT) in the diagnosis of HPS.Materials and Methods:We have enrolled 100 consecutive cirrhosis patients referred to the Liver Clinic of a tertiary care centre of India for >1 year. The Child-Pugh score and the MELD score were used to determine the severity of cirrhosis. All the patients underwent transthoracic contrast echocardiography, arterial blood gas measurements on room air, 6MWT, and chest imaging.Results:A total of 100 patients were included in the study after fulfilling the inclusion criteria. HPS was present in 21 out of 100 patients (21%). Median (twenty fifth to seventy fifth percentile) MELD score in patients with HPS was 29 (26–33), which was significantly higher as compared to patients without HPS 22 (14.5–26); P <.0001. The 6MWT was positive in 20 (95.23%) HPS patients, while only 1 patient (4.77%) of HPS had negative 6MWT. If 6MWT is positive, then there was 76.92% probability of HPS and if 6MWT is negative, then 98.65% chances of no HPS.Conclusion:The 6MWT is a simple and effective screening test for HPS, it helps in identifying the patients early who have a potential to deteriorate. This simple intervention would help in prioritizing patients for liver transplantation as liver transplant is the only effective treatment for HPS.

Impact of hepatopulmonary syndrome in liver transplantation candidates and the role of angiogenesis.

Hepatopulmonary syndrome affects 10-30% of patients with cirrhosis and portal hypertension. We evaluated the serum angiogenic profile of hepatopulmonary syndrome and assessed the clinical impact of hepatopulmonary syndrome in patients evaluated for liver transplantation. The Pulmonary Vascular Complications of Liver Disease 2 study was a multicentre, prospective cohort study of adults undergoing their first liver transplantation evaluation. Hepatopulmonary syndrome was defined as an alveolar-arterial oxygen gradient ≥15 mmHg (≥20 mmHg if age >64 years), positive contrast-enhanced transthoracic echocardiography and absence of lung disease. We included 85 patients with hepatopulmonary syndrome and 146 patients without hepatopulmonary syndrome. Patients with hepatopulmonary syndrome had more complications of portal hypertension and slightly higher Model for End-Stage Liver Disease-Na score compared to those without hepatopulmonary syndrome (median (interquartile range) 15 (12-19) versus 14 (10-17), p=0.006). Hepatopulmonary syndrome patients had significantly lower 6-min walk distance and worse functional class. Hepatopulmonary syndrome patients had higher circulating angiopoietin 2, Tie2, tenascin C, tyrosine protein kinase Kit (c-Kit), vascular cell adhesion molecule 1 and von Willebrand factor levels, and lower E-selectin levels. Patients with hepatopulmonary syndrome had an increased risk of death (hazard ratio 1.80, 95% CI 1.03-3.16, p=0.04), which persisted despite adjustment for covariates (hazard ratio 1.79, 95% CI 1.02-3.15, p=0.04). This association did not vary based on levels of oxygenation, reflecting the severity of hepatopulmonary syndrome. Hepatopulmonary syndrome was associated with a profile of abnormal systemic angiogenesis, worse exercise and functional capacity, and an overall increased risk of death.

Predictors of outcomes following liver transplant in hepatopulmonary syndrome: An OPTN database analysis

Hepatopulmonary syndrome (HPS) is a type of pulmonary vascular disease occurring exclusively in those with underlying liver disease, associated with significant mortality in patients awaiting liver transplantation (LT). LT is curative in HPS, and these patients are granted Model for End Stage Liver Disease (MELD) exception points to expedite LT. The purpose of this study is to use multivariable competing risk Accelerated Failure Time models and propensity matching to examine the relationship between pre-LT hypoxemia and post-LT outcomes in HPS. We performed a retrospective cohort study of UNOS/OPTN database of all adult patients undergoing LT between January 1, 2006 and January 12, 2020. Pre-LT PaO2 was significantly associated with post-LT mortality in HPS, with each 1 mmHg increase in PaO2 significantly decreasing the risk of post-LT mortality (coefficient 0.039, HR = 0.95, p = 0.001). HPS patients with a pre-LT PaO2 < 54 mmHg demonstrated increased mortality following LT as compared to matched non-HPS cirrhotic patients. We conclude that HPS patients with a PaO2, 54 mmHg are at increased risk of post-LT mortality and may identify high-risk patients who would benefit from additional resources during LT, and that the effects of HPS MELD exception points to optimize post-LT outcomes should be continuously re-evaluated.

Hepatopulmonary syndrome delays postoperative recovery and increases pulmonary complications after hepatectomy.

This study attempted to investigate the impact of hepatopulmonary syndrome (HPS) on postoperative outcomes in hepatitis B virus-induced hepatocellular carcinoma (HBV-HCC) patients. HBV-HCC patients undergoing primary curative hepatectomy for HCC in our hospital were diagnosed with HPS by contrast-enhanced echocardiography (CEE) and arterial blood gas analysis. Patients were divided into HPS, intrapulmonary vascular dilation (IPVD) (patients with positive CEE results and normal oxygenation) and control (patients with negative CEE results) groups. Baseline information, perioperative clinical data and postoperative pulmonary complications (PPCs) were compared among all groups. Cytokines in patient serums from each group (n = 8) were also assessed. Eighty-seven patients undergoing hepatectomy from October 2019 to January 2020 were analyzed. The average time in the postanaesthesia care unit (112.10 ± 38.57 min) and oxygen absorption after extubation [34.0 (14.5-54.5) min] in the HPS group was longer than in IPVD [81.81 ± 26.18 min and 16.0 (12.3-24.0) min] and control [93.70 ± 34.06 min and 20.5 (13.8-37.0) min] groups. There were no significant differences in oxygen absorption time after extubation between HPS and control groups. The incidence of PPCs, especially bi-lateral pleural effusions in the HPS group (61.9%), was higher than in IPVD (12.5%) and control (30.0%) groups. Increased serum levels of the growth-regulated oncogene, monocyte chemoattractant protein, soluble CD40 ligand and interleukin 8 might be related to delayed recovery in HPS patients. HPS patients with HBV-HCC suffer delayed postoperative recovery and are at higher risk for PPCs, especially bi-lateral pleural effusions, which might be associated with changes in certain cytokines.

Diagnosis of Hepatopulmonary Syndrome in a Large Integrated Health System

Data on the accuracy of the diagnosis of hepatopulmonary syndrome (HPS) in cirrhosis is limited. We evaluated the clinical characteristics of patients with International Classification of Diseases (ICD) codes for hepatopulmonary syndrome (HPS) in a large integrated health system. A retrospective review of encounters was performed of all patients with ICD-9-CM and/or ICD-10-CM diagnosis of cirrhosis and HPS from 2014-2019 in a multi-state health system. Demographics and cardiopulmonary testing closest to the time of HPS diagnosis were recorded. HPS was defined using standard criteria. A total of 42,749 unique individuals with cirrhosis were identified. An ICD diagnosis of HPS was found in 194 patients (0.45%), of which 182 had clinically confirmed cirrhosis. 143 (78.5%) underwent contrast-enhanced transthoracic echocardiography, and 98 (54%) had delayed shunting. Among them, 61 patients had a documented arterial blood gas, with 53 showing abnormal oxygenation (A-a gradient of >15 mm Hg). 12 were excluded due to significant pulmonary function test abnormalities and abnormal oxygenation from other cardiopulmonary diseases. Ultimately, 41 (22.5%) fulfilled the criteria for HPS. When stratifying those with an ICD code diagnosis of HPS into HPS, no HPS and indeterminate HPS groups, based on standard diagnostic criteria for HPS, we found that the confirmed HPS patients had similar complications except for less portopulmonary hypertension, worse gas exchange, less cardiopulmonary disease and were more often diagnosed in transplant centers. The diagnosis of HPS by ICD code is made in an extremely small subset of a sizeable cirrhotic cohort. When made, only a minority of these patients meet diagnostic criteria. Our findings highlight the need for improved education and more effective screening algorithms.

Prevalence and determinants of hepatopulmonary syndrome in decompensated chronic liver disease.

One of the severe complications of liver disease is hepatopulmonary syndrome (HPS). There is paucity in literature regarding the various factors associated with the development of HPS. This study was conducted to analyze the prevalence and determinants of HPS among patients with decompensated chronic liver disease (CLD). This study was a cross-sectional-observational study conducted in a tertiary care center. Decompensated CLD patients admitted for pre-liver transplant workup were included in the study. Demographic data, clinical findings, and biochemical and hematologic parameters were collected. Pulse oximetry, arterial blood gas analysis, bubble contrast echocardiogram, diffusion capacity of the lungs for carbon monoxide (DLCO), and spirometry were done to get the needed parameters. All data were entered into a Microsoft Excel sheet and analyzed using the statistical software SPSS for Windows, version 22.0. Among 64 subjects, 58 were men (90.6%). Mean age was 54.5years. HPS was present in 26 (40.6%) patients. Platypnea and orthodeoxia were present more oftenin HPS patients. DLCO was significantly impaired among patients with HPS. Portopulmonary hypertension was seen in 8 (12.5%) subjects with no difference between HPS and non-HPS patients. Subjects with HPS had more severe liver disease. A model for end-stage liver disease (MELD)-Na score > 19 was associated with HPS (sensitivity 73.08%, specificity 65.79%, PPV 59.4%, and NPV 78.1%). Multivariate analysis (binary logistic regression) revealed that a higher MELD-Na score, hepatic encephalopathy, and impaired DLCO were independently associated with HPS. HPS is associated with more severe liver disease (as per Child-Turcotte-Pugh [CTP] stage and MELD-Na score). There was no relation between HPS and causesof CLD. Higher MELD-Na score, hepatic encephalopathy, impaired DLCO, clubbing, and spider naevi were independently associated with HPS.

Reduced circulating BMP10 and BMP9 and elevated endoglin are associated with disease severity, decompensation and pulmonary vascular syndromes in patients with cirrhosis.

BackgroundBMP9, originating from the liver, and BMP10 are circulating BMPs that preserve vascular endothelial integrity. We assessed BMP9, BMP10 and soluble endoglin (sEng) levels and their relationships to liver disease severity and associated pulmonary vascular syndromes in a cohort of well-characterised liver disease patients.MethodsPlasma samples from patients with liver disease (n = 83) and non-disease controls (n = 21) were assayed for BMP9, BMP10 and sEng. Levels were also assessed in a separate cohort of controls (n = 27) and PoPH patients (n = 8). Expression of mRNA and immunohistochemical staining was undertaken in liver biopsy specimens. Plasma BMP activity was assessed using an endothelial cell bioassay.FindingsPlasma BMP9 and BMP10 levels were normal in patients with compensated cirrhosis or fibrosis without cirrhosis, but markedly reduced in patients with decompensated cirrhosis, including those with hepatopulmonary syndrome (HPS) or portopulmonary hypertension (PoPH). Liver biopsy specimens revealed reduced mRNA expression and immunostaining for these ligands. Patient plasma samples with reduced BMP9 and BMP10 levels exhibited low BMP activity that was restored with exogenous BMP9. Endoglin mRNA expression was increased in cirrhotic livers and elevated circulating sEng levels in PoPH and HPS patients suggested increased endothelial sEng shedding in these syndromes.InterpretationPlasma BMP9 and BMP10 levels are reduced in decompensated cirrhosis, leading to reduced circulating BMP activity on the vascular endothelium. The pulmonary complications of cirrhosis, PoPH and HPS, are associated with markedly reduced BMP9 and BMP10 and increased sEng levels, suggesting that supplementation with exogenous ligands might be a therapeutic approach for PoPH and HPS.

Resources Utilization After Liver Transplantation in Patients With and Without Hepatopulmonary Syndrome: Cleveland Clinic Experience.

Background.Patients with hepatopulmonary syndrome (HPS) reportedly experience posttransplant morbidity and require more resources to care during perioperative period. The exact incremental increase of resources utilization compared with non-HPS population remains unknown.Methods.In this single-center retrospective investigation, we compared the perioperative resources utilization of HPS patients undergoing orthotopic liver transplant (n = 28) to cohort without HPS (n = 739). Potential confounding variables were adjusted in the analysis and the multivariable log-linear regression were used.Results.The overall hospital costs for HPS patients were about 27% higher compared with non-HPS patients (the ratio of geometric means, 1.27; 98.3% confidence interval, 1.09-1.47; P < 0). HPS diagnosis was independently associated with both longer intensive care unit stay (P < 0.001) and hospital stay (P < 0.001). The odds of being discharged to extended care facility were about 15 times higher for HPS patients comparing to non-HPS patients (odds ratio, 14.9; 97.5% confidence interval, 4.98-44.29; P < 0.001). There were no differences observed in odds of being readmitted to the hospital within 6 mo after the transplant (P = 0.75).Conclusions.HPS diagnosis was associated with longer intensive care unit stay, hospital stay, and increased hospital cost, together with higher odds of being discharged to extended care facility compared with non-HPS patients.

Hepatocyte-derived exosomal MiR-194 activates PMVECs and promotes angiogenesis in hepatopulmonary syndrome

Hepatopulmonary syndrome (HPS) is a serious vascular complication in the setting of liver disease. Factors produced by the liver are essential to regulate pulmonary angiogenesis in the pathogenesis of HPS; however, the pathogenic mechanisms of pulmonary angiogenesis are not fully understood. We investigated the role of HPS rat serum exosomes (HEs) and sham-operated rat serum exosomes (SEs) in the regulation of angiogenesis. We found that HEs significantly enhance PMVEC proliferation, migration, and tube formation. We further identified miR-194 was the most notably increased miRNA in HEs compared to SEs. Once released, hepatocyte-derived exosomal miR-194 was internalized by PMVECs, leading to the promotion of PMVEC proliferation, migration, and tube formation through direct targeting of THBS1, STAT1, and LIF. Importantly, the pathogenic role of exosomal miR-194 in initiating angiogenesis was reversed by P53 inhibition, exosome secretion inhibition or miR-194 inhibition. Additionally, high levels of miR-194 were found in serum exosomes and were positively correlated with P(A-a)O2 in HPS patients and rats. Thus, our results highlight that the exosome/miR-194 axis plays a critical pathologic role in pulmonary angiogenesis, representing a new therapeutic target for HPS.

Cyclooxygenase-2 regulates HPS patient serum induced-directional collective HPMVEC migration via PKC/Rac signaling pathway

Hepatopulmonary syndrome (HPS) is a serious complication in patients with advanced liver disease. The pathological pulmonary angiogenesis contributes to the progression of HPS. Importantly, directional collective migration of endothelial cells is a critical event for pathological angiogenesis. Previously, we have demonstrated that the over-expression of Cyclooxygenase-2 (COX-2) was an important factor in the experimental HPS. However, the role of COX-2 in the directional collective migration of human pulmonary microvascular endothelial cells (HPMVECs) is unclear. Our study aims to evaluate the potential effect of COX-2 in the directional collective migration of HPMVECs under the stimulation of HPS patient serum. In this study, 9 patients with stable liver cirrhosis were screened for presence of HPS. We confirmed that HPS patient serum dramatically promoted the directional collective migration and angiogenesis of HPMVECs, while the COX-2 selective antagonist parecoxib significantly inhibited the directional collective migration of HPMVEC under the stimulation of HPS patient serum. In addition, HPS patient serum significantly upregulated the phosphorylation of PKC and promoted the activation of Rac via COX-2/PGE2 signaling pathway. Notably, silencing PKC activation attenuated the directional collective migration of HPMVEC induced by HPS patient serum. In conclusion, these results indicate that PKC/Rac signaling induced by COX-2 modulates collective directional migration of HPMVEC during pathological pulmonary angiogenesis in HPS patients.

11. Spectrum and manifestation of hepato-pulmonary syndrome in 150 consecutive living related pediatric liver transplantation

Background and Aims: Liver transplantation (LT) is challenging in hepatopulmonary syndrome (HPS). Pre-operative pO2 < 50 mmHg and MAAscan showing >20%shunting are believed to predict mortality post-LT. We aim to study profile, impact and outcome of HPS in pediatric-LT and to study use of inhaled nitric oxide (iNO) for refractory hypoxemia post-LT. Methods: Retrospective analysis. Age < 18 years. Study period: 2010-2016. HPS severity graded by 2 methods: pO2 room air (mild: >80 mmHg, moderate: 60–80 mmHg, severe: 50–60 mmHg, very severe <50 mmHg) and CE-ECHO (some shunt:few bubbles, significant shunt:dense opacification). Post- operative course and outcomes-were-studied. iNO used for refractory post-operative hypoxemia (sPO2 < 85% despite FiO2 100%) as per institutionally developed protocol. Results: Out of 150 patients studied, 23 had HPS. Mean age: 6.5 years. Biliary atresia was commonest underlying etiology (52.2%). By oxygenation criteria: Mild HPS:1 2 (52.2%), moderate-HPS:4 (17.3%), severe-HPS:1 (4.7%); very-severe HPS: 6 (26.1%). By CE-ECHO 12 (52.2%) had significant and 11 (47.8%) had some shunt. On MAAscan shunt-fraction ranged from 19.9–73%-it didn’t correlate with severity of pre-operative hypoxemia (p = 0.623), length of ICU stay (LOS) (p = 0.245) or hospital stay (p = 0.479). Patients with very severeHPS (n = 6) had higher LOS (p = 0.031) and duration of oxygen requirement (p = 0.001) compared to rest HPS patients. 4 of these 6 patients had-pO2 < 45 mmHg: this appeared to-be predictor of stormy post-operative course. One-out-of these 4 died-on 7th post-operative-day due-to intracranial-hemorrhage (ICH). Remaining 3 had refractory post-operative hypoxemia, prolonged-LOS and hospital stay. iNO was used in all 3 cases successfully (mean duration of iNO:26.3days). Incidence of hepatic artery thrombosis in HPS-group was 17.3% compared to 3.1% in non-HPS group (3.1%; p = 0.786). PV-thrombosis occurred in 1 (4.3%) in HPS group. ICH occurred in 2, both had pO2 < 45 mmHg. 1 died on POD7 and other recovered with intact neurological outcome. 1-year survival of HPS-group was 86.9% which was similar to nonHPS group (94.4%, p = 0.88). Conclusions: Pediatric LT in HPS, especially if severe is challenging. With good supportive care, outcomes of HPS and non-HPS patients are comparable. pO2 < 45 mm Hg, predicts a difficult post-operative course, rather than mortality. iNO is a successful strategy to overcome refractory postoperative hypoxemia. The authors have none to declare.

Placental growth factor inhibition targets pulmonary angiogenesis and represents a therapy for hepatopulmonary syndrome in mice.

CBDL in mice induces HPS, which is mediated by PlGF production; αPlGF treatment improves experimental HPS by counteracting pulmonary angiogenesis and might be an attractive therapeutic strategy for human HPS. (Hepatology 2017).

Clinical efficacy of transjugular intrahepatic portosystemic shunt in the treatment of hepatopulmonary syndrome.

Transjugular intrahepatic portosystemic shunt (TIPS) reduces the portal venous pressure of patients with hepatopulmonary syndrome (HPS).To describe the patients who underwent TIPS for the treatment of HPS.A retrospective study was performed on 81 patients with HPS and gastrointestinal hemorrhage treated with TIPS. Thirty patients underwent TIPS through the main portal vein (group A), 24 through the left branch of the portal vein (group B), and 27 through the right branch of the portal vein (group C). The partial pressure of arterial oxygen (PaO2), alveolar-to-arterial oxygen partial pressure gradient (A–aPO2), oxygen saturation (SO2), and complications were recorded and compared. The survival rate for each group was calculated.The technical success rate was 100% in the 3 groups. Preoperative portal vein pressure showed no significant differences between the 3 groups, which was decreased post-TIPS operation. In group A, PaO2 and SO2 were higher in 15 days and 3 months postoperative than preoperative (P < .05), whereas A–aPO2 was lower (P < .05). No difference occurred between 12 months post- and preoperative group. In group C, PaO2 and SO2 did not alter significantly at each time point after operation (P > .05), whereas A–aPO2 decreased at 3 months (P = .041) than preoperative. In group B, all indicators at each follow-up time point after TIPS were improved significantly as compared with the preoperative group (P < .05), which showed an excellent effect on hypoxemia treatment. Although the 1-year survival rate of 3 groups of patients was 92.85%, 90.90%, and 91.67%, respectively, the rate of hepatic encephalopathy and hepatic myelopathy was 33.33% (10/30), 16.67% (4/24), and 33.33% (9/27) after TIPS.TIPS reduced the pressure of the portal vein effectively and alleviated hypoxemia in most HPS patients successfully. Thus, the left branch of the portal vein is optimal for TIPS owing to fewer complications and efficacy in improving PaO2 as compared with the main portal vein and right branch.

Hepatopulmonary Syndrome: Oxidative Stress and Physical Exercise

Hepatopulmonary syndrome (HPS) may be defined by hepatic disease, gas exchange abnormalities that may lead to hypoxaemia, and the presence of pulmonary vascular dilations. The balance between the many substances involved in vasodilation and vasoconstriction is regulated by the liver; thus, liver damage may generate systemic changes throughout the body. The pulmonary tissue may be damaged by reactive oxygen species or nitric oxide. Dyspnoea is the most frequent pulmonary symptom, caused by tissue damage, and may become worse when an individual exercises. In experimental research the surgical model of bile duct ligation is the optimal model to simulate the typical lung alterations present in HPS, which results in an increase in oxidative stress in hepatic and pulmonary tissues. In liver injury, the muscular system may also be damaged, for example sarcopenia may seriously aggravate cirrhosis and is associated with cirrhotic patient mortality. Muscular changes can be explained by the actions of myostatin and insulin-like growth factor and the increase in body levels of ammonia. As a result of impaired cardiopulmonary and muscular conditions, HPS patients may exhibit a low exercise tolerance, low muscle strength, and low functionality. Liver disease can contribute to HPS oxidative stress and is one of the main factors responsible for the reduction of gas exchange. Physical exercise can be performed as a way of modifying this pathophysiological state. Studies that have investigated physical exercise as a therapy for cirrhosis suggest that this approach may be beneficial for cirrhotic patients, primarily with regard to muscular and cardiorespiratory injuries.

Hepatopulmonary Syndrome and Liver Transplantation: A Recent Review of the Literature.

A severe and common pulmonary vascular complication of liver disease is hepatopulmonary syndrome (HPS). It is a triad of liver dysfunction and/or portal hypertension, intrapulmonary vascular dilatations, and increased alveolar-arterial oxygen gradient. Prevalence varies according to various study groups from 4%–47%. While the most common presenting symptom of HPS is dyspnea, it is usually asymptomatic, and thus all liver transplant candidates should be screened for its presence. Pulse oximetry is a useful screening method, but arterial blood gas examination is the gold standard. If there is an abnormal P (A-a)O2 gradient, microbubble transthoracic echocardiography should be done for diagnosis. Outcome is unpredictable, and there is currently no effective medical therapy. The only effective therapy is considered to be liver transplantation. Complete resolution of HPS after liver transplantation is seen within a year in most HPS patients.

Frequency of Hepatopulmonary Syndrome (HPS) Among Patients With Liver Cirrhosis: A Letter to Editor.

Dear Editor, Hepatopulmonary syndrome (HPS) is a complication of liver disease. It is most frequently related to portal hypertension (with or without cirrhosis), although chronic liver disease of almost any etiology could be related to HPS (1, 2). Moreover, some acute liver diseases are related to HPS, such as ischemic hepatitis (3). HPS can be diagnosed when the following disorders have been approved (1, 4, 5); liver disorder, impaired oxygenation, intrapulmonary vascular anomalies, referred to as intrapulmonary vascular dilatations (IPVDs) and lack of intrinsic cardiopulmonary problem. HPS patients finally develop dyspnea on exertion, at rest, or both, commonly after years of liver disease. Dyspnea may be accompanied by pulmonary findings that are more specific for HPS (1, 6) such as platypnea and orthodeoxia. The frequency of hepatopulmonary syndrome in patients with chronic liver disease is about 4 to 47% regarding the criteria of diagnosis and used methods (7-12). The current study evaluated the prevalence of this complication in patients with cirrhosis. Thirty eight patients with cirrhosis were included in this study. Chest X-ray, air-contrast echocardiography, ABG in supine and standing positions, Tc99 MAA lung perfusion scan, PFT (pulmonary function test), serum bilirubin, PT and albumin were evaluated in patients. Hepatopulmonary syndrome was diagnosed in patients who had intrapulmonary vascular shunting and pulmonary gas exchange abnormalities. Among 38 patients, 28 persons were male (%73.7) and 10 females (%26.3). The mean age was 46.2 ± 13.6 (ranged 18 - 64 years). The most common cause of cirrhosis was hepatitis B. Among 29 patients (%76.3), hepatitis B and among 3 patients (%7.6) hepatitis C was diagnosed. Six patients (%15.8) had cryptogenic cirrhosis. Eleven patients (%28.9) had significant hypoxemia (pa O2 < 70) and 24 patients (%71.1) had not hypoxemia. Using echocardiography, 9 patients (23.7%) had pulmonary shunt. Also using radio isotope scan, 2 patients (%5.3) had pulmonary shunt. No patients with positive results in scan had contrast echocardiography. Therefore, pulmonary shunt frequency was %23.7. Six patients (15.8%) had HPS. Three patients (9.9%) had pulmonary shunt without hypoxemia or elevated p(A-a)O2 that are introduced subclinical HPS or IPVDs. Fourteen patients (%36.8) had child score A, 19 patients (%50) child score B and 5 (%13.2) child score C. The findings of the present study showed the prevalence of HPS and intrapulmonary vascular dilatation syndrome in patients with cirrhosis. Air-contrast echocardiography was more effective in diagnosis of intrapulmonary vascular shunting compared to Tc99 MAA lung perfusion scan. No significant relation was found between sex, age, duration, severity, and primary reason of cirrhosis with hepatopulmonary syndrome, but intrapulmonary vascular shunting was more usual in women patients. Spider angioma, orthodeoxia, low serum albumin, and ascites were determined to be suitable clinical indicators for hepatopulmonary syndrome.