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Robert F, Benchenouf F, Ha MN, Cuomo A, Ottaviani M, Surbier M, Thuillet R, Normand C, Dumont F, Verstuyft C, Fiore F, Guinut F, Humbert M, Coilly A, Gonzales E, Sitbon O, Tu L, Guignabert C, Savale L. Placental growth factor modulates endothelial NO production and exacerbates experimental hepatopulmonary syndrome. JHEP Rep 2025; 7:101297. [PMID: 39980753 PMCID: PMC11840504 DOI: 10.1016/j.jhepr.2024.101297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 11/27/2024] [Accepted: 12/05/2024] [Indexed: 02/22/2025] Open
Abstract
Background & Aims Hepatopulmonary syndrome (HPS) results from portal hypertension, with or without cirrhosis, and is marked by pulmonary vascular dilations leading to severe hypoxemia. Although placental growth factor (PlGF) is important for vascular growth and endothelial function, its role in HPS is unclear. This study investigated the involvement of PlGF in experimental models of HPS and in patients. Methods Circulating PlGF levels were measured in 64 controls and 137 patients with liver disease, with or without HPS. Two rat models, common bile duct ligation (CBDL) and long-term partial portal vein ligation (PPVL), were used. Plgf-knockout (Plgf -/-) rats were generated using CRISPR-Cas9. Lung RNA-sequencing analysis was performed in the CBDL model. The effects of PlGF on endothelial nitric oxide synthase (eNOS) activity in human pulmonary microvascular endothelial cells were also investigated. Results Circulating PlGF levels were significantly higher in patients with cirrhosis compared with healthy controls (29.4 ± 1.2 vs. 20.2 ± 0.8 pg/ml, p <0.0001), but no difference were found between patients with and without HPS. PlGF levels were not elevated in patients with extrahepatic portal hypertension. In Plgf -/- rats, there was a protective effect against CBDL-induced HPS, whereas PPVL-induced HPS severity remained unchanged. RNA sequencing coupled with ingenuity pathway analysis identified significant interactions between PlGF and pulmonary eNOS activity. Following CBDL, Plgf -/- rats showed decreased pulmonary eNOS activity and reduced circulating nitric oxide metabolites. In vitro, PlGF stimulation enhanced eNOS activity in human pulmonary microvascular endothelial cells, whereas PlGF knockdown led to a decrease. Conclusions These findings indicate that PlGF aggravates cirrhosis-induced HPS through modulation of pulmonary eNOS activity, and is not involved in HPS from extrahepatic portal hypertension. Impact and implications This study identified PlGF as a significant contributor to the exacerbation of HPS associated with cirrhosis, through its regulation of pulmonary nitric oxide production. Our findings demonstrated that PlGF deficiency mitigates the severity of both cirrhosis and HPS in the CBDL model, highlighting its potential as a therapeutic target in cirrhosis-induced HPS. Notably, this protective effect was absent in the PPVL model, which induces HPS associated with portal hypertension without cirrhosis. These results open avenues for novel pharmacological interventions aiming to improve outcomes for patients with cirrhosis-induced HPS.
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Affiliation(s)
- Fabien Robert
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - Feriel Benchenouf
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - My Ngoc Ha
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - Alessandra Cuomo
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Mina Ottaviani
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - Maxime Surbier
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - Raphaël Thuillet
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - Corinne Normand
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - Florent Dumont
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - Céline Verstuyft
- Université Paris-Saclay, Centre de Ressource Biologique Paris-Saclay, Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Bicêtre, Le Kremlin Bicêtre, France
| | - Frederic Fiore
- Centre d'Immunophénomique (CIPHE), Aix Marseille Université, INSERM, CNRS, CELPHEDIA, PHENOMIN, Marseille, France
| | | | - Marc Humbert
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de L’hypertension Pulmonaire (PulmoTension), AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Audrey Coilly
- Centre Hépato-Biliaire, AP-HP, Hôpital Paul Brousse, Villejuif, France
- INSERM UMR_S 1193, Hepatinov, University Paris-Saclay, Orsay, France
| | - Emmanuel Gonzales
- INSERM UMR_S 1193, Hepatinov, University Paris-Saclay, Orsay, France
- Pediatric Hepatology and Liver Transplantation Unit, National Reference Centre for Biliary Atresia and Genetic Cholestasis, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Olivier Sitbon
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de L’hypertension Pulmonaire (PulmoTension), AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Ly Tu
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - Christophe Guignabert
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - Laurent Savale
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de L’hypertension Pulmonaire (PulmoTension), AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
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Sayadi A, Duhaut L, Robert F, Savale L, Coilly A. [Hepatopulmonary syndrome]. Rev Med Interne 2024; 45:156-165. [PMID: 37005097 DOI: 10.1016/j.revmed.2023.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 03/07/2023] [Accepted: 03/17/2023] [Indexed: 04/03/2023]
Abstract
The hepatopulmonary syndrome (HPS) is one of the lung diseases associated with cirrhosis and portal hypertension. It should be discussed for any dyspnea in cirrhotic patients. HPS is a pulmonary vascular disease characterized by intrapulmonary vascular dilatations (IPVD). The pathogenesis is complex and seems to rely on communications between the portal and pulmonary circulations. The diagnosis is based on a triad of liver disease and portal hypertension, evidence of IPVDs, and impaired gas exchange (alveolar-arterial oxygen difference [A-aO2]≥15mmHg). HPS impairs prognosis (23% survival at 5years) and patients' quality of life. Liver transplantation (LT) allows regression of IPDVD in almost 100% of cases, normalization of gas exchange and improves survival with a 5-year post-LT survival between 76 and 87%. It is the only curative treatment, indicated in patients with severe HPS, defined by an arterial partial pressure of oxygen (PaO2) below 60mmHg. When LT is not indicated or feasible, long-term oxygen therapy may be proposed as a palliative treatment. A better understanding of the pathophysiological mechanisms is needed to improve the therapeutic possibilities in a near future.
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Affiliation(s)
- A Sayadi
- UMR-S 1193, hôpital Paul-Brousse, centre hépato-biliaire, université Paris-Saclay, AP-HP, 94800 Villejuif, France
| | - L Duhaut
- UMR-S 1193, hôpital Paul-Brousse, centre hépato-biliaire, université Paris-Saclay, AP-HP, 94800 Villejuif, France
| | - F Robert
- Inserm UMR_S 999, 94270 Le Kremlin-Bicêtre, France
| | - L Savale
- Inserm UMR_S 999, 94270 Le Kremlin-Bicêtre, France; Service de pneumologie, hôpital Bicêtre, université Paris-Saclay, AP-HP, 94270 Le Kremlin-Bicêtre, France
| | - A Coilly
- UMR-S 1193, hôpital Paul-Brousse, centre hépato-biliaire, université Paris-Saclay, AP-HP, 94800 Villejuif, France.
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Baweja S, Kumari A, Negi P, Tomar A, Tripathi DM, Mourya AK, Rastogi A, Subudhi PD, Thangariyal S, Kumar G, Kumar J, Reddy GS, Sood AK, Vashistha C, Sarohi V, Bihari C, Maiwall R, Sarin SK. Hepatopulmonary syndrome is associated with low sphingosine-1-phosphate levels and can be ameliorated by the functional agonist fingolimod. J Hepatol 2023; 79:167-180. [PMID: 36996943 DOI: 10.1016/j.jhep.2023.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 02/28/2023] [Accepted: 03/03/2023] [Indexed: 04/01/2023]
Abstract
BACKGROUND & AIMS Hepatopulmonary syndrome (HPS) is characterised by a defect in arterial oxygenation induced by pulmonary vascular dilatation in patients with liver disease. Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator, suppresses vasodilation by reducing nitric oxide (NO) production. We investigated the role of S1P in patients with HPS and the role of fingolimod as a therapeutic option in an experimental model of HPS. METHODS Patients with cirrhosis with HPS (n = 44) and without HPS (n = 89) and 25 healthy controls were studied. Plasma levels of S1P, NO, and markers of systemic inflammation were studied. In a murine model of common bile duct ligation (CBDL), variations in pulmonary vasculature, arterial oxygenation, liver fibrosis, and inflammation were estimated before and after administration of S1P and fingolimod. RESULTS Log of plasma S1P levels was significantly lower in patients with HPS than in those without HPS (3.1 ± 1.4 vs. 4.6 ± 0.2; p <0.001) and more so in severe intrapulmonary shunting than in mild and moderate intrapulmonary shunting (p <0.001). Plasma tumour necrosis factor-α (76.5 [30.3-91.6] vs. 52.9 [25.2-82.8]; p = 0.02) and NO (152.9 ± 41.2 vs. 79.2 ± 29.2; p = 0.001) levels were higher in patients with HPS than in those without HPS. An increase in Th17 (p <0.001) and T regulatory cells (p <0.001) was observed; the latter inversely correlated with plasma S1P levels. In the CBDL HPS model, fingolimod restored pulmonary vascular injury by increasing the arterial blood gas exchange and reducing systemic and pulmonary inflammation, resulting in improved survival (p = 0.02). Compared with vehicle treatment, fingolimod reduced portal pressure (p <0.05) and hepatic fibrosis and improved hepatocyte proliferation. It also induced apoptotic death in hepatic stellate cells and reduced collagen formation. CONCLUSIONS Plasma S1P levels are low in patients with HPS and even more so in severe cases. Fingolimod, by improving pulmonary vascular tone and oxygenation, improves survival in a murine CBDL HPS model. IMPACT AND IMPLICATIONS A low level of plasma sphingosine-1-phosphate (S1P) is associated with severe pulmonary vascular shunting, and hence, it can serve as a marker of disease severity in patients with hepatopulmonary syndrome (HPS). Fingolimod, a functional agonist of S1P, reduces hepatic inflammation, improves vascular tone, and thus retards the progression of fibrosis in a preclinical animal model of HPS. Fingolimod is being proposed as a potential novel therapy for management of patients with HPS.
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Affiliation(s)
- Sukriti Baweja
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.
| | - Anupama Kumari
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Preeti Negi
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Arvind Tomar
- Department of Pulmonary Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Dinesh Mani Tripathi
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Akash Kumar Mourya
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Aayushi Rastogi
- Department of Epidemiology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - P Debishree Subudhi
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Swati Thangariyal
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Guresh Kumar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Jitendra Kumar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - G Srinivasa Reddy
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Arun Kumar Sood
- Department of Cardiology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Chitranshu Vashistha
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | | | - Chhagan Bihari
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv Kumar Sarin
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India; Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
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Baweja S, Kumari A, Negi P, Thangariyal S, Subudhi PD, Gautam S, Mittal A, Bihari C. Vascular Extracellular Vesicles Indicate Severe Hepatopulmonary Syndrome in Cirrhosis. Diagnostics (Basel) 2023; 13:diagnostics13071272. [PMID: 37046489 PMCID: PMC10093463 DOI: 10.3390/diagnostics13071272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/10/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Background: 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. Methods: 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. Results: 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. Conclusion: 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.
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Gera A, Pant D. Preoperative Assessment and Optimization of Liver Transplant Patients: Pulmonary Issues. PERI-OPERATIVE ANESTHETIC MANAGEMENT IN LIVER TRANSPLANTATION 2023:147-161. [DOI: 10.1007/978-981-19-6045-1_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Raevens S, Boret M, Fallon MB. Hepatopulmonary syndrome. JHEP REPORTS : INNOVATION IN HEPATOLOGY 2022; 4:100527. [PMID: 36035361 PMCID: PMC9403489 DOI: 10.1016/j.jhepr.2022.100527] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/10/2022] [Accepted: 06/15/2022] [Indexed: 11/25/2022]
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.
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Certain MC, Robert F, Baron A, Sitbon O, Humbert M, Guignabert C, Tu L, Savale L. Syndrome hépatopulmonaire : prévalence, physiopathologie et implications cliniques. Rev Mal Respir 2022; 39:84-89. [DOI: 10.1016/j.rmr.2022.02.055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 01/05/2022] [Indexed: 11/28/2022]
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Del Valle K, DuBrock HM. Hepatopulmonary Syndrome and Portopulmonary Hypertension: Pulmonary Vascular Complications of Liver Disease. Compr Physiol 2021; 11:3281-3302. [PMID: 34636408 DOI: 10.1002/cphy.c210009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pulmonary vascular disease is a frequent complication of chronic liver disease and portal hypertension, affecting up to 30% of patients. There are two distinct pulmonary vascular complications of liver disease: hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH). HPS affects 25% of patients with chronic liver disease and is characterized by intrapulmonary vasodilatation and abnormal arterial oxygenation. HPS negatively impacts quality of life and is associated with a 2-fold increased risk of death compared to controls with liver disease without HPS. Angiogenesis, endothelin-1 mediated endothelial dysfunction, monocyte influx, and alveolar type 2 cell dysfunction seem to play important roles in disease pathogenesis but there are currently no effective medical therapies. Fortunately, HPS resolves following liver transplant (LT) with improvements in hypoxemia. POPH is a subtype of pulmonary arterial hypertension (PAH) characterized by an elevated mean pulmonary arterial pressure and pulmonary vascular resistance in the setting of normal left-sided filling pressures. POPH affects 5% to 6% of patients with chronic liver disease. Although the pathogenesis has not been fully elucidated, endothelial dysfunction, inflammation, and estrogen signaling have been identified as key pathways involved in disease pathogenesis. POPH is typically treated with PAH targeted therapy and may also improve with liver transplantation in selected patients. This article highlights what is currently known regarding the diagnosis, management, pathobiology, and outcomes of HPS and POPH. Ongoing research is needed to improve understanding of the pathophysiology and outcomes of these distinct and often misunderstood pulmonary vascular complications of liver disease. © 2021 American Physiological Society. Compr Physiol 11:1-22, 2021.
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Pellegrini JR, Munshi R, Patel P, Pelletier B, Patel P, Mustacchia P. The Impact of Hepatic Cirrhosis on Chronic Obstructive Pulmonary Disease in the United States: A Nationwide Analysis. Cureus 2021; 13:e16368. [PMID: 34408927 PMCID: PMC8361533 DOI: 10.7759/cureus.16368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/13/2021] [Indexed: 11/24/2022] Open
Abstract
We aimed to study the impact of Hepatic Cirrhosis (HC) on chronic obstructive pulmonary disease (COPD). Our study is a retrospective cohort study using the 2016-2017 National Readmission Database (NRD). NRD is part of the Healthcare Cost and Utilization Project (HCUP), organized and supported by means of the Agency for Healthcare Research and Quality (AHRQ). Patients were included if they were 18 years or older and had a principal diagnosis of COPD based on International Classification of Diseases, Tenth Revision (ICD-10- CM) codes and had a secondary diagnosis of HC. A total of 505,004 patients were included in the study with a diagnosis of COPD, 6196 (1.23%) of whom had HC. HC was found to be more common amongst male patients between the ages of 50 and 65 years. Medicare beneficiaries with high comorbidity burden, lower socioeconomic status, and those who received treatment in a large urban teaching hospital also had higher rates of HC. Patients with HC and COPD correlated to an increase of in-hospital mortality (adjusted odds ratio (aOR: 2.21, p<0.001) and 30-day hospital readmission rate (aOR: 1.23, p<0.001) compared with patients without HC. The in-hospital mortality rate was higher during readmission compared with index admissions (5.01% versus 2.16%; p<0.001). In addition, HC was associated with higher morbidity including prolonged mechanical ventilation (aOR: 1.39, p<0.001), resource utilization with prolong length of stay (LOS) (adjusted mean difference (aMD: 0.51, p<0.001), higher total hospitalization charges (aMD: 4967, p<0.001), and costs (aMD: 1200, p<0.001). Both patient groups had similar odds of being intubated (aOR: 1.18, p-0.13), tracheostomy (aOR: 0.81, p-069) and bronchoscopy rates (aOR: 1.27, p-0.36). The most common causes of hospital readmission were found to be COPD with acute exacerbation (19.7%), sepsis, unspecified organism (6.0%, acute and chronic respiratory failure with hypoxia (4.2%), acute on chronic systolic heart failure (3.9%), and hepatic failure, unspecified coma (3.1%). Various autonomous prognosticators of readmission were sex (particularly female), alcohol dependence, LOS greater than 7 days, lower comorbidity burden, and discharge to short term hospital or against medical advice. On the other hand, males, patients without a history of alcohol dependence, greater comorbidity burden, and LOS fewer than 3 days, were less likely to be readmitted. We found that HC is related to higher in-hospital mortality, LOS, increased mechanical ventilation, resource utilization with prolonged LOS, hospital costs, odds of intubation, and tracheostomy and bronchoscopy rates. Our study aims to shed light on the impact of HC on COPD in hopes to improve future management.
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Affiliation(s)
| | - Rezwan Munshi
- Internal Medicine, Nassau University Medical Center, East Meadow, USA
| | - Pranavi Patel
- Internal Medicine, Nassau University Medical Center, East Meadow, USA
| | - Brandon Pelletier
- Internal Medicine, Nassau University Medical Center, East Meadow, USA
| | - Palakkumar Patel
- Internal Medicine, Nassau University Medical Center, East Meadow, USA
| | - Paul Mustacchia
- Gastroenterology and Hepatology, Nassau University Medical Center, East Meadow, USA
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A Role for Alveolar Exhaled Nitric Oxide Measurement in the Diagnosis of Hepatopulmonary Syndrome. J Clin Gastroenterol 2020; 54:278-283. [PMID: 31306341 DOI: 10.1097/mcg.0000000000001246] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
GOALS The authors sought to characterize predominantly alveolar exhaled nitric oxide (eNO) in hepatopulmonary syndrome (HPS) compared with non-HPS, changes after liver transplantation, and diagnostic properties. BACKGROUND HPS is defined by liver disease, intrapulmonary vascular dilatations (IPVDs), and hypoxemia. Rat models and small human studies suggest that NO overproduction may cause IPVDs. STUDY A retrospective review of the Canadian HPS Database (2007 to 2017) and prospective eNO measurement (main outcome) in healthy controls (measurement expiratory flow, 200 mL/s). HPS was defined as: (1) liver disease; (2) contrast echocardiography consistent with IPVDs; and (3) partial pressure of arterial oxygen <70 mm Hg with alveolar-arterial gradient >20 mm Hg; subclinical HPS as criteria (1) and (2) only; and no HPS as criterion (1) only. Current smokers and subjects with asthma or pulmonary hypertension were excluded. A linear mixed effects model was used to compare eNO between groups and before and after transplantation. RESULTS eNO was 10.4±0.7 ppb in HPS (n=26); 8.3±0.6 ppb in subclinical HPS (n=38); 7.1±1.0 ppb in no HPS (n=15); and 5.6±0.7 ppb in controls (n=30) (P<0.001). eNO decreased from 10.9±0.8 ppb preliver to 6.3±0.8 ppb postliver transplant (n=6 HPS, 6 subclinical HPS) (P<0.001). eNO <6 ppb was 84.4% (73.1% to 92.2%) sensitive and ≥12 ppb was 78.1% (69.4% to 85.3%) specific for HPS (vs. subclinical HPS). CONCLUSIONS HPS subjects have higher alveolar eNO than non-HPS subjects, levels normalize with liver transplantation. Applying eNO cutoff values may aid in HPS diagnosis.
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Shi YJ, Mckiernan P, Soltys K, Mazariegos G, Wang WL. Surgical closure of large splenorenal shunt may accelerate recovery from hepato-pulmonary syndrome in liver transplant patients. World J Emerg Med 2020; 11:60-63. [PMID: 31893005 DOI: 10.5847/wjem.j.1920-8642.2020.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Yan-Jun Shi
- Department of Hepatobiliary & Pancreas Surgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China.,Thomas E. Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation, Department of Transplant Surgery, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Patrick Mckiernan
- Thomas E. Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation, Department of Transplant Surgery, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Kyle Soltys
- Thomas E. Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation, Department of Transplant Surgery, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - George Mazariegos
- Thomas E. Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation, Department of Transplant Surgery, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Wei-Lin Wang
- Department of Hepatobiliary & Pancreas Surgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China
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Measurement of Exhaled Nitric Oxide in Cirrhotic Patients with Esophageal and Gastric Varices. BIOMED RESEARCH INTERNATIONAL 2019; 2019:9673162. [PMID: 31781658 PMCID: PMC6874994 DOI: 10.1155/2019/9673162] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 10/08/2019] [Accepted: 10/11/2019] [Indexed: 11/17/2022]
Abstract
Background and aims. This study aimed to detect exhaled nitric oxide (eNO) level in cirrhotic patients and explore the correlation between eNO levels and the severity of cirrhosis. Methods. Patients were enrolled to analyze the relationship of eNO with noncirrhosis, cirrhosis, and complications of decompensated cirrhosis. We explored the potential predictive values of eNO in different states of cirrhosis. Results. The eNO levels were significantly increased in cirrhotic patients compared with noncirrhotic patients (14 (10-18) vs 8 (6-13) ppb, P < 0.001). The eNO level was increased in those with ascites (15 (14-22) vs 13 (10-18) ppb, P=0.026), with portal vein thrombosis (19.5 (11.75-22) vs 13.5 (10-17) ppb, P=0.032), or with the mucosal red-color sign of esophageal and gastric varices (EGV) (16.5 (10-21.75) vs 13 (10-14.75) ppb, P=0.041). Among cirrhotic patients undergoing hepatic venous pressure gradient (HVPG) measurement, the eNO level was significantly increased in the high-HVPG group (HVPG >12 mm Hg) compared with the low-HVPG group (6 mm Hg ≤ HVPG ≤ 12 mm Hg) (15 (11.75-19.25) vs 10 (8-14) ppb, P=0.011). Conclusions. The eNO level was increased in cirrhotic patients, especially in those complicated with ascites, portal vein thrombosis, mucosal red-color sign of varices, and high HVPG.
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Bosco AD, Schedler FB, Colares JR, Schemitt EG, Hartmann RM, Forgiarini Junior LA, Dias AS, Marroni NP. Melatonin effects on pulmonary tissue in the experimental model of Hepatopulmonary Syndrome. ACTA ACUST UNITED AC 2019; 45:e20170164. [PMID: 31166552 PMCID: PMC6715043 DOI: 10.1590/1806-3713/e20170164] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 08/12/2018] [Indexed: 01/25/2023]
Abstract
Objective: To evaluate the pulmonary alterations of animals with Hepatopulmonary Syndrome (HPS) submitted to Biliary Duct Ligature (BDL), as well as the antioxidant effect of Melatonin (MEL). Methods: Sixteen male Wistar rats, divided into four Sham groups: BDL group, Sham + MEL group and BDL + MEL. The pulmonary and hepatic histology, lipoperoxidation and antioxidant activity of lung tissue, alveolar-arterial O2 difference and lung / body weight ratio (%) were evaluated. Results: When comparing the groups, could be observed an increase of vasodilation and pulmonary fibrosis in the BDL group and the reduction of this in relation to the BDL + MEL group. It was also observed significant changes in the activity of catalase, ApCO2, ApO2 in the LBD group when compared to the other groups. Conclusion: The use of MEL has been shown to be effective in reducing vasodilation, fibrosis levels and oxidative stress as well as gas exchange in an experimental HPS model.
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Affiliation(s)
| | | | | | - Elisângela Gonçalves Schemitt
- . Hospital de Clínicas de Porto Alegre, Porto Alegre (RS) Brasil.,. Universidade Federal do Rio Grande do Sul, Porto Alegre (RS) Brasil
| | - Renata Minuzzo Hartmann
- . Hospital de Clínicas de Porto Alegre, Porto Alegre (RS) Brasil.,. Universidade Federal do Rio Grande do Sul, Porto Alegre (RS) Brasil
| | | | - Alexandre Simões Dias
- . Hospital de Clínicas de Porto Alegre, Porto Alegre (RS) Brasil.,. Universidade Federal do Rio Grande do Sul, Porto Alegre (RS) Brasil
| | - Norma Possa Marroni
- . Hospital de Clínicas de Porto Alegre, Porto Alegre (RS) Brasil.,. Universidade Federal do Rio Grande do Sul, Porto Alegre (RS) Brasil
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14
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Lejealle C, Paradis V, Bruno O, de Raucourt E, Francoz C, Soubrane O, Lebrec D, Bedossa P, Valla D, Mal H, Vilgrain V, Durand F, Rautou PE. Evidence for an Association Between Intrahepatic Vascular Changes and the Development of Hepatopulmonary Syndrome. Chest 2019; 155:123-136. [DOI: 10.1016/j.chest.2018.09.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Revised: 08/21/2018] [Accepted: 09/05/2018] [Indexed: 02/06/2023] Open
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16
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Raevens S, Fallon MB. Potential Clinical Targets in Hepatopulmonary Syndrome: Lessons From Experimental Models. Hepatology 2018; 68:2016-2028. [PMID: 29729196 PMCID: PMC6204081 DOI: 10.1002/hep.30079] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 07/20/2018] [Accepted: 04/27/2018] [Indexed: 12/12/2022]
Abstract
Hepatopulmonary syndrome (HPS) is a relatively common and potentially severe pulmonary complication of cirrhosis with increased risk of mortality. In experimental models, a complex interaction between pulmonary endothelial cells, monocytes, and the respiratory epithelium, which produces chemokines, cytokines, and angiogenic growth factors, causes alterations in the alveolar microvasculature, resulting in impaired oxygenation. Model systems are critical for evaluating mechanisms and for preclinical testing in HPS, due to the challenges of evaluating the lung in the setting of advanced liver disease in humans. This review provides an overview of current knowledge and recent findings in the rodent common bile duct ligation model of HPS, which recapitulates many features of human disease. We focus on the concepts of endothelial derangement, monocyte infiltration, angiogenesis, and alveolar type II cell dysfunction as main contributors and potential targets for therapy.
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Affiliation(s)
- Sarah Raevens
- Department of Gastroenterology and Hepatology – Hepatology Research Unit, Ghent University – Ghent University Hospital, Ghent, Belgium
- Department of Internal Medicine, University of Arizona College of Medicine, Phoenix, Arizona, USA
| | - Michael B. Fallon
- Department of Internal Medicine, University of Arizona College of Medicine, Phoenix, Arizona, USA
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17
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Davies T, Wythe S, O'Beirne J, Martin D, Gilbert-Kawai E. Review article: the role of the microcirculation in liver cirrhosis. Aliment Pharmacol Ther 2017; 46:825-835. [PMID: 29023881 DOI: 10.1111/apt.14279] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2017] [Revised: 04/11/2017] [Accepted: 08/06/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Intrahepatic microvascular derangements and microcirculatory dysfunction are key in the development of liver cirrhosis and its associated complications. While much has been documented relating to cirrhosis and the dysfunction of the microcirculation in the liver parenchyma, far less is known about the state of the extrahepatic microcirculation and the role this may have in the pathogenesis of multiple organ failure in end stage liver cirrhosis. AIM To provide an update on the role of the microcirculation in the pathophysiology of cirrhosis and its associated complications and briefly discuss some of the imaging techniques which may be used to directly investigate the microcirculation. METHODS A Medline literature search was conducted using the following search terms: 'cirrhosis', 'microcirculation', 'circulation', 'systemic', 'inflammation', 'peripheral', 'hepatorenal' and 'hepatopulmonary'. RESULTS Significant heterogeneous microvascular alterations exist in patients with cirrhosis. Data suggest that the systemic inflammation, associated with advanced cirrhosis, induces microcirculatory dysregulation and contributes to haemodynamic derangement. The resultant vasoconstriction and hypoperfusion in the systemic extrahepatic microvasculature, is likely to be instrumental in the pathophysiology of organ failure in decompensated cirrhosis, however the mechanistic action of vasoactive agents used to correct the circulatory disturbance of advanced cirrhosis is poorly understood. CONCLUSIONS Further research into the role of the microcirculation in patients with liver cirrhosis, will improve physicians understanding of the pathophysiology of cirrhosis, and may provide a platform for real time evaluation of an individual's microcirculatory response to vasoactive mediators, thus guiding their therapy.
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Affiliation(s)
- T Davies
- Intensive Care Department, Royal Free Hospital, London, UK.,UCLH NIHR Biomedical Research Centre, Institute of Sport and Exercise Health, University College London Centre for Altitude Space and Extreme Environment Medicine, London, UK
| | - S Wythe
- Intensive Care Department, Royal Free Hospital, London, UK.,UCLH NIHR Biomedical Research Centre, Institute of Sport and Exercise Health, University College London Centre for Altitude Space and Extreme Environment Medicine, London, UK
| | - J O'Beirne
- Department of Hepatology, Nambour General Hospital, Sunshine Coast Hospital and Health Service, Nambour, Qld, Australia
| | - D Martin
- Intensive Care Department, Royal Free Hospital, London, UK.,UCLH NIHR Biomedical Research Centre, Institute of Sport and Exercise Health, University College London Centre for Altitude Space and Extreme Environment Medicine, London, UK
| | - E Gilbert-Kawai
- Intensive Care Department, Royal Free Hospital, London, UK.,UCLH NIHR Biomedical Research Centre, Institute of Sport and Exercise Health, University College London Centre for Altitude Space and Extreme Environment Medicine, London, UK
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18
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Iqbal S, Smith KA, Khungar V. Hepatopulmonary Syndrome and Portopulmonary Hypertension: Implications for Liver Transplantation. Clin Chest Med 2017; 38:785-795. [PMID: 29128026 DOI: 10.1016/j.ccm.2017.08.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PoPH) represent serious pulmonary complications of advanced liver diseases. Orthotopic liver transplantation (OLT) is capable of completely resolving the underlying abnormalities associated with HPS. On the other hand, post-OLT response in patients with PoPH is less predictable, although heavily influenced by pre-OLT mean pulmonary arterial pressure. It remains the case that the opportunity to reverse 2 potentially fatal organ dysfunctions in the liver and the lung make HPS and PoPH more than worthy for further clinical investigations.
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Affiliation(s)
- Shaz Iqbal
- Department of Medicine, General Internal Medicine Division, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - Kerri Akaya Smith
- Department of Medicine, Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, 834 West Gates Building, Philadelphia, PA 19104, USA
| | - Vandana Khungar
- Department of Medicine, Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street 2 Dulles, Philadelphia, PA 19104, USA.
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19
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Neviere R, Trinh-Duc P, Hulo S, Edme JL, Dehon A, Boleslawski E, Dharancy S, Lebuffe G. Predictive value of exhaled nitric oxide and aerobic capacity for sepsis complications after liver transplantation. Transpl Int 2016; 29:1307-1316. [PMID: 27649520 DOI: 10.1111/tri.12861] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 04/27/2016] [Accepted: 09/12/2016] [Indexed: 12/17/2022]
Abstract
Our objective was to investigate the predictive value of fractional nitric oxide (NO) concentration in exhaled breath (FeNO) and aerobic capacity (peak VO2 ) for postoperative sepsis in liver transplantation candidates. Patients were identified and charts of all consecutive patients were prospectively reviewed. Bacterial sepsis represented the commonest postoperative complications (30%), which was attributed to peritonitis, pneumonia, and catheter-related infections. Preoperative FeNO and peak VO2 values were lower in patients with postoperative sepsis. Patients with sepsis required higher needs for mechanical ventilation and ICU length of stay. Inverse correlation was found between logarithmically FeNO-transformed data and systolic pulmonary artery pressure (r = -0.348; P = 0.018). Multivariate analyses using bootstrap sampling method indicated that odds of sepsis were associated with lower values of peak exercise VO2 [OR = 0.790 (0.592; 0.925)] and reduced log(FeNo) [OR = 0.027 (0.001; 0.451)], but not with higher MELD scores [OR = 1.141 (0.970; 1.486)]. By evaluating the cutoff for the ROC curves in each bootstrap resampling, median and 95% confidence interval were calculated for peak VO2 : 17 [16.2; 22] ml/kg/min and FeNO: 17.2 [13.0; 33.9] ppb. We conclude that low peak exercise VO2 and reduced FeNO may help identify patients who are at risk to develop perioperative sepsis.
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Affiliation(s)
- Remi Neviere
- Service d'Explorations Fonctionnelles Respiratoires, Hôpital Calmette, CHU Lille, Lille, France.,Département de Physiologie, Faculté of Médicine - INSERM U995, Université Lille, Lille, France
| | | | - Sébastien Hulo
- Service d'Explorations Fonctionnelles Respiratoires, Hôpital Calmette, CHU Lille, Lille, France.,Département de Médecine du Travail, EA4483 Faculté of Médicine, Université Lille, Lille, France
| | - Jean Louis Edme
- Service d'Explorations Fonctionnelles Respiratoires, Hôpital Calmette, CHU Lille, Lille, France.,Département de Médecine du Travail, EA4483 Faculté of Médicine, Université Lille, Lille, France
| | - Aurélie Dehon
- Pôle d'Anesthésie Réanimation ADRU, CHU Nîmes, Lille, France
| | - Emmanuel Boleslawski
- Service de Chirurgie Digestive et de Transplantation, Hôpital Huriez, CHU Lille, Lille, France
| | - Sébastien Dharancy
- Service des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Huriez, CHU Lille, Lille, France
| | - Gilles Lebuffe
- Pôle d'Anesthésie Réanimation, Université de Lille, CHU Lille, EA7365 - GRITA - Groupe de Recherche sur les Formes Injectables et technologies Associées, Lille, France
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20
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Left Ventricular Dilation and Pulmonary Vasodilatation after Surgical Shunt for Treatment of Pre-Sinusoidal Portal Hypertension. PLoS One 2016; 11:e0154011. [PMID: 27119143 PMCID: PMC4847763 DOI: 10.1371/journal.pone.0154011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 04/07/2016] [Indexed: 02/07/2023] Open
Abstract
Objective The aim of this study was to prospectively investigate the long-term cardiovascular and pulmonary hemodynamic effects of surgical shunt for treatment of portal hypertension (PH) due to Schistosomiasis mansoni. Location The University of São Paulo Medical School, Brazil; Public Practice. Methods Hemodynamic evaluation was performed with transesophageal Doppler and contrast-enhanced echocardiography (ECHO) on twenty-eight participants with schistosomal portal hypertension. Participants were divided into two groups according to the surgical procedure used to treat their schistosomal portal hypertension within the last two years: group 1—distal splenorenal shunt (DSRS, n = 13) and group 2—esophagogastric devascularization and splenectomy (EGDS, n = 15). Results The cardiac output (5.08 ± 0.91 L/min) and systolic volume (60.1 ± 5.6 ml) were increased (p = 0.001) in the DSRS group. DSRS participants had a significant increase (p < 0.0001) in their left ventricular end-systolic and end-diastolic diameters as well as in their left ventricular end-diastolic and end-systolic volumes (p < 0.001) compared with the preoperative period. No statistically significant difference was found in the patients who underwent EGDS. ECHO revealed intrapulmonary vasodilatation (IPV) in 18 participants (64%), 9 DSRS and 9 EGDS (p > 0.05). Conclusions The late increase in the cardiac output, stroke volume and left ventricular diameters demonstrated left ventricular dilatation after a distal splenorenal shunt. ECHO revealed a greater prevalence for IPV in patients with schistosomiasis than has previously been described in patients with PH from liver cirrhosis.
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Rodriguez-Roisin R, Bartolome SD, Huchon G, Krowka MJ. Inflammatory bowel diseases, chronic liver diseases and the lung. Eur Respir J 2016; 47:638-50. [PMID: 26797027 DOI: 10.1183/13993003.00647-2015] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Accepted: 11/12/2015] [Indexed: 12/12/2022]
Abstract
This review is devoted to the distinct associations of inflammatory bowel diseases (IBD) and chronic liver disorders with chronic airway diseases, namely chronic obstructive pulmonary disease and bronchial asthma, and other chronic respiratory disorders in the adult population. While there is strong evidence for the association of chronic airway diseases with IBD, the data are much weaker for the interplay between lung and liver multimorbidities. The association of IBD, encompassing Crohn's disease and ulcerative colitis, with pulmonary disorders is underlined by their heterogeneous respiratory manifestations and impact on chronic airway diseases. The potential relationship between the two most prevalent liver-induced pulmonary vascular entities, i.e. portopulmonary hypertension and hepatopulmonary syndrome, and also between liver disease and other chronic respiratory diseases is also approached. Abnormal lung function tests in liver diseases are described and the role of increased serum bilirubin levels on chronic respiratory problems are considered.
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Affiliation(s)
- Roberto Rodriguez-Roisin
- Servei de Pneumologia (Institut del Tòrax), Hospital Clínic, Institut Biomédic August Pi i Sunyer (IDIBAPS), Ciber Enfermedades Respiratorias (CIBERES), Universitat de Barcelona, Barcelona, Spain
| | - Sonja D Bartolome
- Pulmonary and Critical Care Medicine, UT Southwestern Medical Center, Dallas, TX, USA
| | - Gérard Huchon
- Service de Pneumologie, Université Paris 5, Paris, France
| | - Michael J Krowka
- Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
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Malinovschi A, Ludviksdottir D, Tufvesson E, Rolla G, Bjermer L, Alving K, Diamant Z. Application of nitric oxide measurements in clinical conditions beyond asthma. Eur Clin Respir J 2015; 2:28517. [PMID: 26672962 PMCID: PMC4653314 DOI: 10.3402/ecrj.v2.28517] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 07/05/2015] [Indexed: 02/01/2023] Open
Abstract
Fractional exhaled nitric oxide (FeNO) is a convenient, non-invasive method for the assessment of active, mainly Th2-driven, airway inflammation, which is sensitive to treatment with standard anti-inflammatory therapy. Consequently, FeNO serves as a valued tool to aid diagnosis and monitoring in several asthma phenotypes. More recently, FeNO has been evaluated in several other respiratory, infectious, and/or immunological conditions. In this short review, we provide an overview of several clinical studies and discuss the status of potential applications of NO measurements in clinical conditions beyond asthma.
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Affiliation(s)
- Andrei Malinovschi
- Department of Medical Sciences: Clinical Physiology, Uppsala University, Uppsala, Sweden;
| | - Dora Ludviksdottir
- Department of Respiratory Medicine and Sleep, Landspitali University Hospital, Reykjavik, Iceland
| | - Ellen Tufvesson
- Department of Respiratory Medicine and Allergology, Institute for Clinical Science, Lund University, Lund, Sweden
| | - Giovanni Rolla
- Department of Medical Sciences, Allergology and Clinical Immunology, University of Torino, Torino, Italy
| | - Leif Bjermer
- Department of Respiratory Medicine and Allergology, Institute for Clinical Science, Lund University, Lund, Sweden
| | - Kjell Alving
- Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden
| | - Zuzana Diamant
- Department of Respiratory Medicine and Allergology, Institute for Clinical Science, Lund University, Lund, Sweden.,Department of Clinical Pharmacy & Pharmacology, University Medical Centre Groningen, Groningen, The Netherlands.,Department of General Practice, University Medical Centre Groningen, Groningen, The Netherlands.,QPS Netherlands, Groningen, The Netherlands
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Abstract
Hepatopulmonary syndrome (HPS) is a pulmonary complication observed in patients with chronic liver disease and/or portal hypertension, attributable to an intrapulmonary vascular dilatation that may induce severe hypoxemia. Microvascular dilation and angiogenesis in the lung have been identified as pathologic features that drive gas exchange abnormalities in experimental HPS. Pulse oximetry is a useful screening test for HPS, which can guide subsequent use of arterial blood gases. Contrast-enhanced echocardiography, perfusion lung scanning, and pulmonary arteriography are three currently used diagnostic imaging modalities that identify the presence of intrapulmonary vascular abnormalities. The presence of HPS increases mortality and impairs quality of life, but is reversible with liver transplantation. No medical therapy is established as effective for HPS. At the present time, liver transplantation is the only available treatment for HPS.
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Affiliation(s)
- Yong Lv
- Department of Liver Disease, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China,
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Raevens S, Geerts A, Van Steenkiste C, Verhelst X, Van Vlierberghe H, Colle I. Hepatopulmonary syndrome and portopulmonary hypertension: recent knowledge in pathogenesis and overview of clinical assessment. Liver Int 2015; 35:1646-60. [PMID: 25627425 DOI: 10.1111/liv.12791] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 01/17/2015] [Indexed: 12/14/2022]
Abstract
Hepatopulmonary syndrome and portopulmonary hypertension are cardiopulmonary complications, which are not infrequently seen in patients with liver disease and/or portal hypertension. These entities are both clinically and pathophysiologically different: the hepatopulmonary syndrome is characterized by abnormal pulmonary vasodilation and right-to-left shunting resulting in gas exchange abnormalities, whereas portopulmonary hypertension is caused by pulmonary artery vasoconstriction leading to hemodynamic failure. As both hepatopulmonary syndrome and portopulmonary hypertension are associated with significantly increased morbidity and mortality, and as these patients are commonly asymptomatic, all liver transplantation candidates should be actively screened for the presence of these two complications. The aim of is this review is to provide an overview on the hepatopulmonary syndrome and portopulmonary hypertension with primary focus on diagnosis and recent knowledge regarding pathogenesis and therapeutic targets.
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Affiliation(s)
- Sarah Raevens
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Anja Geerts
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Christophe Van Steenkiste
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium.,Department of Gastroenterology and Hepatology, Maria Middelares Hospital, Ghent, Belgium
| | - Xavier Verhelst
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Hans Van Vlierberghe
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Isabelle Colle
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium.,Department of Gastroenterology and Hepatology, Algemeen Stedelijk Ziekenhuis ASZ, Aalst, Belgium
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DuBrock HM, Bankier AA, Silva M, Litmanovich DE, Curry MP, Washko GR. Pulmonary Vessel Cross-sectional Area before and after Liver Transplantation: Quantification with Computed Tomography. Acad Radiol 2015; 22:752-9. [PMID: 25770631 DOI: 10.1016/j.acra.2015.01.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Revised: 01/23/2015] [Accepted: 01/25/2015] [Indexed: 10/23/2022]
Abstract
RATIONALE AND OBJECTIVES Pulmonary vascular complications of liver disease have a substantial impact on morbidity and mortality in patients who undergo liver transplant. The effect of liver transplantation on the pulmonary vasculature in patients without pulmonary vascular disease, however, has not been described. This study was undertaken to characterize the regional effect of liver transplant on the cross-sectional area (CSA) of pulmonary vessels. MATERIALS AND METHODS We performed a single-center, retrospective, cohort study of patients who had a liver transplant between 2002 and 2012 and who had chest computed tomography scans within 1 year before and after transplant. Using ImageJ software, we measured the CSA of small pulmonary vessels (0-5 mm(2)) and the total lung CSA to calculate the percent CSA of pulmonary vessels <5 mm (%CSA<5) at the level of the aortic arch, carina, and right inferior pulmonary vein (RIPV). Pretransplant and posttransplant, %CSA<5 were compared, and associations of pretransplant %CSA<5 with clinical parameters were measured. RESULTS There was a significant decrease in %CSA<5 at the level of the RIPV (0.19% [interquartile range {IQR}, 0.15-0.26] before vs. 0.15% [IQR, 0.12-0.21] after; P = .0003), with a median change of -16.2% (IQR, -39.3 to 3.9) posttransplant. Changes at the level of the aortic arch and carina were not significant. Pretransplant RIPV %CSA<5 was not significantly correlated with severity of liver disease or oxygenation but was inversely correlated with percent change in %CSA<5 (r = -0.39; P = .0039). CONCLUSIONS This is the first study to describe a significant regional change in the pulmonary vessels of patients without known pulmonary vascular disease who undergo liver transplant.
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Younis I, Sarwar S, Butt Z, Tanveer S, Qaadir A, Jadoon NA. Clinical characteristics, predictors, and survival among patients with hepatopulmonary syndrome. Ann Hepatol 2015. [PMID: 25864216 DOI: 10.1016/s1665-2681(19)31275-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatopulmonary syndrome (HPS) is a complication of advanced liver disease. The impact of HPS on survival is not clearly understood. MATERIAL AND METHODS A prospective study was carried out at Department of Medicine, King Edward Medical University Lahore from June 2011 to May 2012. Patients with cirrhosis of liver were evaluated for presence of HPS with arterial blood gas analysis and saline bubble echocardiography. All patients were followed for 6 months for complications and mortality. Cox regression analysis was done to evaluate role of HPS on patient survival. RESULTS 110 patients were included in the study. Twenty-nine patients (26%) had HPS. MELD score was significantly higher (p < 0.01) in patients with HPS (18.93 ± 3.51) as compared to that in patients without HPS (13.52 ± 3.3). Twenty two (75.9%) patients of Child class C, 5 (17.2%) patients of Child class B and 2 (6.9%) patients of Child class A had HPS (P 0.03). The clinical variables associated with presence of HPS were spider nevi, digital clubbing, dyspnea, and platypnea. HPS significantly increased mortality during six month follow up period (HR: 2.47, 95% CI: 1.10- 5.55). Child-Pugh and MELD scores were also associated with increased mortality. HPS was no longer associated with mortality when adjustment was done for age, gender, Child-Pugh, and MELD scores (HR: 0.44, 95% CI: 0.14-1.41). Both the Child-Pugh and MELD scores remained significantly associated with mortality in the multivariate survival analysis. CONCLUSIONS HPS indicates advanced liver disease. HPS does not affect mortality when adjusted for severity of cirrhosis.
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Affiliation(s)
| | | | - Zeeshan Butt
- Prince George's Hospital Center, Cheverly MD, USA
| | | | | | - Nauman Arif Jadoon
- Center for Biomedical Research, Lahore, Pakistan; Nishtar Medical College Hospital, Multan-Pakistan
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Horvatits T, Drolz A, Roedl K, Herkner H, Ferlitsch A, Perkmann T, Müller C, Trauner M, Schenk P, Fuhrmann V. Von Willebrand factor antigen for detection of hepatopulmonary syndrome in patients with cirrhosis. J Hepatol 2014; 61:544-9. [PMID: 24798623 DOI: 10.1016/j.jhep.2014.04.025] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Revised: 04/15/2014] [Accepted: 04/17/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Hepatopulmonary syndrome (HPS) occurs in 20-30% of patients with liver cirrhosis and is associated with a >2 fold increased mortality. Endothelial dysfunction seems to play a central role in its pathogenesis. von Willebrand factor antigen (vWF-Ag), an established marker of endothelial dysfunction, is significantly elevated in patients with liver cirrhosis, portal hypertension, and in experimental HPS. Aim of the present study was to evaluate the impact of vWF-Ag as a screening marker for presence of HPS in patients with stable cirrhosis. METHODS 145 patients with stable liver cirrhosis were screened for presence of HPS in this prospective cohort type cross sectional diagnostic study. vWF-Ag and SaO2 levels were assessed at time of screening for HPS. Criteria of HPS were fulfilled in 31 (21%) patients. RESULTS vWF-Ag levels were significantly higher in patients with HPS compared to patients without HPS (p<0.001). Furthermore, vWF-Ag correlated significantly with gas exchange in HPS positive patients (p<0.05). vWF-Ag is an independent predictor of HPS after correction for sex, age, model for endstage-liver disease (MELD), and hepatic venous pressure gradient (HVPG) (OR per 1% increase of vWF-Ag: 1.02, 95% CI: 1.00-1.04, p<0.05). The best cut-off was 328% at a sensitivity of 100% and specificity of 53.5%; positive predictive value: 36.9%; negative predictive value: 100%. CONCLUSIONS HPS is associated with elevated vWF-Ag levels. vWF-Ag may be a useful screening tool for early detection of HPS. Further studies investigating vWF-Ag in HPS will be needed to confirm our findings.
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Affiliation(s)
- Thomas Horvatits
- Department of Internal Medicine 3, Division of Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Austria; Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas Drolz
- Department of Internal Medicine 3, Division of Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Austria; Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Kevin Roedl
- Department of Internal Medicine 3, Division of Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Austria
| | - Harald Herkner
- Department of Internal Medicine 3, Division of Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Austria
| | - Arnulf Ferlitsch
- Department of Internal Medicine 3, Division of Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Austria
| | - Thomas Perkmann
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Christian Müller
- Department of Internal Medicine 3, Division of Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Department of Internal Medicine 3, Division of Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Austria
| | - Peter Schenk
- Department of Internal Medicine 3, Division of Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Austria
| | - Valentin Fuhrmann
- Department of Internal Medicine 3, Division of Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Austria; Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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Abstract
The hepatopulmonary syndrome (HPS) is a pulmonary complication of cirrhosis and/or portal hypertension whereby patients develop hypoxemia as a result of alterations in pulmonary microvascular tone and architecture. HPS occurs in up to 30% of patients with cirrhosis. Although the degree of hypoxemia does not reliably correlate with the severity of liver disease, patients with HPS have a higher mortality than do patients with cirrhosis without the disorder. There has been progress into defining the mechanisms that lead to hypoxemia in HPS, but to date there are no therapeutic options for HPS aside from liver transplantation.
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Horvatits T, Drolz A, Rutter K, Kluge S, Fuhrmann V. [Pulmonary complications in liver diseases]. Med Klin Intensivmed Notfmed 2014; 109:235-9. [PMID: 24763525 DOI: 10.1007/s00063-013-0319-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Accepted: 03/19/2014] [Indexed: 01/13/2023]
Abstract
Pulmonary-hepatic vascular disorders are frequent complications in patients with portal hypertension and cirrhosis. Hepatopulmonary syndrome (HPS), portopulmonary hypertension (POPH), and hepatic hydrothorax are relevant disease entities in these patients. HPS occurs in up to 30 % of patients with cirrhosis and is associated with a more than 2-fold increased mortality. The diagnosis of HPS should be established early by arterial blood gas analysis and contrast-enhanced echocardiography, whereas POPH is diagnosed by the presence of pulmonary arterial hypertension evaluated via right heart catheterization and the presence of portal hypertension. Therapeutic options include initiation of long-term oxygen therapy and liver transplantation in patients with severe HPS. Patients with POPH should receive targeted medical therapies with endothelin receptor antagonists, phosphodiesterase-5 inhibitors and/or prostanoids. In contrast, β-blockers should be avoided. This review summarizes current knowledge regarding pulmonary-hepatic vascular disorders, with a focus on HPS.
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Affiliation(s)
- T Horvatits
- Klinik für Intensivmedizin, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Deutschland
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The successful use of inhaled nitric oxide in the management of severe hepatopulmonary syndrome after orthotopic liver transplantation. Case Reports Hepatol 2014; 2014:415109. [PMID: 25374726 PMCID: PMC4208388 DOI: 10.1155/2014/415109] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Accepted: 12/22/2013] [Indexed: 01/19/2023] Open
Abstract
Hepatopulmonary syndrome (HPS) is characterized by pulmonary vasodilation and subsequent hypoxemia in the setting of hepatic dysfunction. There is currently no pharmacologic intervention that has been shown to significantly affect outcomes and liver transplantation remains the mainstay of therapy. Unfortunately, patients undergoing liver transplantation are at high risk of significant hypoxemia and mortality in the early postoperative period. In the following case series, we present two cases of patients with severe HPS who underwent liver transplantation and experienced marked hypoxemia in the early postoperative period. In both cases, we successfully treated the patients with inhaled nitric oxide for their severe refractory life-threatening hypoxemia which led to immediate and dramatic improvements in their oxygenation. Although the use of inhaled nitric oxide in patients with HPS has been sporadically reported in pediatric literature and in animal studies, to our knowledge, our cases are the first recorded in adult patients.
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31
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Yang W, Zhang J, Hu B, Wu W, Venter J, Alpini G, Fallon MB. The role of receptor tyrosine kinase activation in cholangiocytes and pulmonary vascular endothelium in experimental hepatopulmonary syndrome. Am J Physiol Gastrointest Liver Physiol 2014; 306:G72-80. [PMID: 24200956 PMCID: PMC3920086 DOI: 10.1152/ajpgi.00178.2013] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Pulmonary vascular dilation and angiogenesis underlie experimental hepatopulmonary syndrome (HPS) induced by common bile duct ligation (CBDL) and may respond to receptor tyrosine kinase (RTK) inhibition. Vascular endothelial growth factor-A (VEGF-A) expression occurs in proliferating cholangiocytes and pulmonary intravascular monocytes after CBDL, the latter contributing to angiogenesis. CBDL cholangiocytes also produce endothelin-1 (ET-1), which triggers lung vascular endothelin B receptor-mediated endothelial nitric oxide synthase (eNOS) activation and pulmonary intravascular monocyte accumulation. However, whether RTK pathway activation directly regulates cholangiocyte and pulmonary microvascular alterations in experimental HPS is not defined. We assessed RTK pathway activation in cholangiocytes and lung after CBDL and the effects of the type II RTK inhibitor sorafenib in experimental HPS. Cholangiocyte VEGF-A expression and ERK activation accompanied proliferation and increased hepatic and circulating ET-1 levels after CBDL. Sorafenib decreased each of these events and led to a reduction in lung eNOS activation and intravascular monocyte accumulation. Lung monocyte VEGF-A expression and microvascular Akt and ERK activation were also found in vivo after CBDL, and VEGF-A activated Akt and ERK and angiogenesis in rat pulmonary microvascular endothelial cells in vitro. Sorafenib inhibited VEGF-A-mediated signaling and angiogenesis in vivo and in vitro and improved arterial gas exchange and intrapulmonary shunting. RTK activation in experimental HPS upregulates cholangiocyte proliferation and ET-1 production, leading to pulmonary microvascular eNOS activation, intravascular monocyte accumulation, and VEGF-A-mediated angiogenic signaling pathways. These findings identify a novel mechanism in cholangiocytes through which RTK inhibition ameliorates experimental HPS.
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Affiliation(s)
- Wenli Yang
- Division of Gastroenterology, Hepatology and Nutrition, Dept. of Internal Medicine, The Univ. of Texas Health Science Center at Houston, 6431 Fannin St., MSB 4.234, Houston, TX 77030-1501.
| | - Junlan Zhang
- 1Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas;
| | - Bingqian Hu
- 1Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas;
| | - Wei Wu
- 1Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas;
| | - Julie Venter
- 2Department of Medicine, Texas A&M Health Science Center, Temple, Texas; and
| | - Gianfranco Alpini
- 3Research, Central Texas Veterans Health Care System, Scott & White Digestive Disease Research Center, Scott & White, Department of Medicine, Division of Gastroenterology, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Michael B. Fallon
- 1Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas;
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32
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Horvatits T, Fuhrmann V. Therapeutic options in pulmonary hepatic vascular diseases. Expert Rev Clin Pharmacol 2013; 7:31-42. [DOI: 10.1586/17512433.2014.857598] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Pharmacological treatment for hepatopulmonary syndrome. BIOMED RESEARCH INTERNATIONAL 2013; 2013:670139. [PMID: 24102057 PMCID: PMC3786536 DOI: 10.1155/2013/670139] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 07/30/2013] [Accepted: 08/12/2013] [Indexed: 12/12/2022]
Abstract
AIM Hepatopulmonary syndrome is a pulmonary dysfunction in the context of liver cirrhosis characterized by arterial deoxygenation. Affected patients have increased morbidity and mortality, and many of them expire before undergoing liver transplantation. Therefore, finding medical therapy as a bridge to transplantation or as a final treatment is necessary. In this study, we aimed to review the current literature about pharmacological options available for treatment of hepatopulmonary syndrome. METHODS A PubMED and Scopus search was conducted in January 2013 on the English literature published in any time period to find human and animal studies reporting pharmacological therapy of hepatopulmonary syndrome. RESULTS Out of 451 studies, 29 relevant articles were included. The number of patients, type, dose, duration, and mechanism of drugs in these studies was extracted and summarized separately. Most of pharmacologic agents act through inhibition of nitric oxide synthase and reduction in nitric oxide production, inactivation of endothelin-1, and treatment of bacterial translocation and pulmonary angiogenesis. CONCLUSION Several drugs have been applied for the treatment of HPS with conflicting results. However, no large randomized trial has been conducted probably due to low number of patients. Multicentered clinical trials are necessary to investigate these drugs.
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34
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Polavarapu N, Tripathi D. Liver in cardiopulmonary disease. Best Pract Res Clin Gastroenterol 2013; 27:497-512. [PMID: 24090938 DOI: 10.1016/j.bpg.2013.06.020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Accepted: 06/12/2013] [Indexed: 01/31/2023]
Abstract
Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PoPH) are two fascinating and incompletely understood pulmonary vascular conditions seen in the setting of cirrhotic patients. Of the two HPS is more common and is primarily caused by pulmonary vasodilatation resulting in hypoxaemia and hyperdynamic circulation. PoPH is less common and conversely, pulmonary vasoconstriction and vascular remodelling occurs resulting in increased pulmonary vascular resistance. However, both conditions can co-exist and it is usually PoPH which develops in a patient with pre-existing HPS. Although these two pulmonary conditions are not common complications of chronic liver diseases, the treatment options are mainly limited to liver transplantation. Cirrhotic cardiomyopathy is closely related to haemodynamic changes in portal hypertension. The key features are normal cardiac pressures at rest, with reduced ability to compensate for physiological or iatrogenic stresses such as drug therapy or TIPSS. There is no effective therapy and outcomes after liver transplantation are variable.
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Affiliation(s)
- Naveen Polavarapu
- Liver Unit, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham B15 2TH, UK
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35
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Grace JA, Angus PW. Hepatopulmonary syndrome: update on recent advances in pathophysiology, investigation, and treatment. J Gastroenterol Hepatol 2013. [PMID: 23190201 DOI: 10.1111/jgh.12061] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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 ET(B) 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.
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Affiliation(s)
- Josephine A Grace
- Department of Medicine, Austin Health, The University of Melbourne, Melbourne, Victoria, Australia.
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36
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Abstract
Hepatopulmonary syndrome (HPS) is a serious vascular complication of liver disease that occurs in 5-32% of patients with cirrhosis. The presence of HPS markedly increases mortality. No effective medical therapies are currently available and liver transplantation is the only established treatment option for HPS. The definition and diagnosis of HPS are established by the presence of a triad of liver disease with intrapulmonary vascular dilation that causes abnormal arterial gas exchange. Experimental biliary cirrhosis induced by common bile duct ligation in the rat reproduces the pulmonary vascular and gas exchange abnormalities of human HPS and serves as a pertinent animal model. Pulmonary microvascular dilation and angiogenesis are two central pathogenic features that drive abnormal pulmonary gas exchange in experimental HPS, and thus might underlie HPS in humans. Defining the mechanisms involved in the microvascular alterations of HPS has the potential to lead to effective medical therapies. This Review focuses on the current understanding of the pathogenesis, clinical features and management of HPS.
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Affiliation(s)
- Junlan Zhang
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, 6431 Fannin Street, MSB 4.234, Houston, TX 77030-1501, USA
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37
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Update on new aspects of the renin-angiotensin system in liver disease: clinical implications and new therapeutic options. Clin Sci (Lond) 2012; 123:225-39. [PMID: 22548407 DOI: 10.1042/cs20120030] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The RAS (renin-angiotensin system) is now recognized as an important regulator of liver fibrosis and portal pressure. Liver injury stimulates the hepatic expression of components of the RAS, such as ACE (angiotensin-converting enzyme) and the AT(1) receptor [AngII (angiotensin II) type 1 receptor], which play an active role in promoting inflammation and deposition of extracellular matrix. In addition, the more recently recognized structural homologue of ACE, ACE2, is also up-regulated. ACE2 catalyses the conversion of AngII into Ang-(1-7) [angiotensin-(1-7)], and there is accumulating evidence that this 'alternative axis' of the RAS has anti-fibrotic, vasodilatory and anti-proliferative effects, thus counterbalancing the effects of AngII in the liver. The RAS is also emerging as an important contributor to the pathophysiology of portal hypertension in cirrhosis. Although the intrahepatic circulation in cirrhosis is hypercontractile in response to AngII, resulting in increased hepatic resistance, the splanchnic vasculature is hyporesponsive, promoting the development of the hyperdynamic circulation that characterizes portal hypertension. Both liver fibrosis and portal hypertension represent important therapeutic challenges for the clinician, and there is accumulating evidence that RAS blockade may be beneficial in these circumstances. The present review outlines new aspects of the RAS and explores its role in the pathogenesis and treatment of liver fibrosis and portal hypertension.
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38
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Bucca C, Cicolin A, Guida G, Heffler E, Brussino L, Rolla G. Exhaled nitric oxide (FENO) in non-pulmonary diseases. J Breath Res 2012; 6:027104. [PMID: 22549131 DOI: 10.1088/1752-7155/6/2/027104] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Exhaled nitric oxide (F(E)NO) represents the only exhaled biomarker that has reached clinical practice even in primary care settings, due to the non-invasiveness of its assessment and ease of repeat measurements, even in patients with severe airflow obstruction. While F(E)NO has been suggested as a readily determined biomarker that can aid in the diagnosis and management of asthma, its potential role in pathophysiology of non-pulmonary diseases is less clear and therefore remains to be established. The purpose of the present review is to highlight the current literature investigating the use of F(E)NO in the diagnosis and management of non-pulmonary diseases.
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Affiliation(s)
- Caterina Bucca
- Department of Clinical Pathophysiology, University of Turin, Italy.
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39
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Afzelius P, Bazeghi N, Bie P, Bendtsen F, Vestbo J, Møller S. Circulating nitric oxide products do not solely reflect nitric oxide release in cirrhosis and portal hypertension. Liver Int 2011; 31:1381-7. [PMID: 21745317 DOI: 10.1111/j.1478-3231.2011.02576.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Patients with cirrhosis often develop a systemic vasodilatation and a hyperdynamic circulation with activation of vasoconstrictor systems such as the renin-angiotensin-aldosterone system (RAAS), and vasopressin. Increased nitric oxide (NO) synthesis has been implicated in the development of this state of vasodilation and pulmonary dysfunction including increased exhaled NO concentrations. Circulating metabolites (NO(x)) may affect the systemic and pulmonary NO-generation. However, the relations of these abnormalities to the haemodynamic changes remain unclear. AIMS The aims of the present study were to measure changes in exhaled NO in relation to circulating NO(x), RAAS, and haemodynamics. METHODS Twenty patients (eight child class A and 12 class B patients) underwent a liver vein catheterization with determination of splanchnic and systemic haemodynamics. Circulating NO(x) and exhaled NO were determined in the supine and sitting positions and related to haemodynamics, RAAS and lung diffusing capacity (D(L)CO). Eight matched healthy individuals served as controls. RESULTS All patients with cirrhosis had portal hypertension. We found no significant difference in exhaled NO between patients and controls and no changes from the supine to the sitting position. Exhaled NO in the patients correlated significantly with plasma volume, heart rate and D(L)CO. NO(x) concentrations were not significantly increased in the patients. NO(x) correlated with portal pressure and haemodynamic indicators of vasodilatation, but not with exhaled NO concentrations. CONCLUSION In patients with moderate cirrhosis, exhaled NO is normal. Circulating NO(x) do not seem to reflect pulmonary and systemic NO release, but NO(x) seems to reflect systemic and splanchnic haemodynamic changes in cirrhosis.
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Affiliation(s)
- Pia Afzelius
- Department of Clinical Physiology and Nuclear Medicine, Hvidovre Hospital, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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40
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Herz S, Puhl G, Spies C, Jörres D, Neuhaus P, von Heymann C. [Perioperative anesthesia management of extended partial liver resection. Pathophysiology of hepatic diseases and functional signs of hepatic failure]. Anaesthesist 2011; 60:103-17. [PMID: 21293838 DOI: 10.1007/s00101-011-1852-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The importance of partial liver resection as a therapeutic option to cure hepatic tumors has increased over the last decades. This has been influenced on the one hand by advances in surgical and anesthetic management resulting in a reduced mortality after surgery and on the other hand by an increased incidence of hepatocellular carcinoma. Nowadays, partial resection of the liver is performed safely and as a routine operation in specialized centers. This article describes the pathophysiological changes secondary to liver failure and assesses the perioperative management of patients undergoing partial or extended liver resection. It looks in detail at the preoperative assessment, the intraoperative anesthetic management including fluid management and techniques to reduce blood loss as well as postoperative analgesia and intensive care therapy.
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Affiliation(s)
- S Herz
- Klinik für Anästhesiologie mit Schwerpunkt operative Intensivmedizin, Charité-Universitätsmedizin Berlin,Campus Virchow-Klinikum und Charité Mitte, Augustenburger Platz 1, Berlin, Germany
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41
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Findlay JY, Fix OK, Paugam-Burtz C, Liu L, Sood P, Tomlanovich SJ, Emond J. Critical care of the end-stage liver disease patient awaiting liver transplantation. Liver Transpl 2011; 17:496-510. [PMID: 21506240 DOI: 10.1002/lt.22269] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Patients with end-stage liver disease awaiting liver transplantation frequently require intensive care admission and management due to either complications of liver failure or to intercurrent illness, particularly infection. Mortality in such patients is high and the development of an illness necessitating intensive care unit management can influence transplant candidacy. Specialized support frequently requires hemodynamic support, mechanical ventilation, and renal support. In this review, areas of management of particular importance to patients with end-stage liver disease in the intensive care unit are discussed. These areas are hepatic encephalopathy, infectious diseases, cardiovascular support, mechanical ventilation, renal support and combined transplantation, and decisions regarding delisting. Current knowledge specific to these patients, when available, is discussed, current practice is described, and areas of uncertainty in the evidence are discussed.
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Affiliation(s)
- James Y Findlay
- Department of Anesthesiology and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.
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42
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Jung JY, Jun DW, Lee JH. Lung diffusion capacity in early cirrhosis: is lung diffusion capacity a predictor of esophageal varices and ascites? Dig Dis Sci 2011; 56:1229-34. [PMID: 20945096 DOI: 10.1007/s10620-010-1406-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2010] [Accepted: 08/18/2010] [Indexed: 12/09/2022]
Abstract
BACKGROUND Varices and ascites are clinical manifestations of hyperdynamic circulation syndrome originating from increased nitric oxide in cirrhosis. Research was conducted in order to find any correlation between lung diffusion capacity and the presence of varices and ascites in cirrhosis. METHODS The study was conducted on a total of 120 subjects. Tests for pulmonary function, including carbon monoxide diffusing capacity (DLCO) and fractional exhaled nitric oxide (FENO), were performed. RESULTS DLCO/alveolar ventilation (VA) values were lower in cirrhosis and chronic liver disease groups than in the control group (3.79 vs. 4.5 vs. 5.1 ml/mmHg/min, p<0.001). DLCO/VA showed a negative correlation with the Child score and the MELD score (r=-0.3 vs. r=-0.41). In patients with varices, the DLCO/VA value was 3.75 ml/mmHg/min, which was lower than the 4.12 ml/mmHg/min observed in patients without varices (p=0.029). FENO levels were higher in the chronic liver disease and liver cirrhosis groups than in the control group. FENO and DLCO showed a negative correlation (r=-0.25, p=0.006). The frequency of significant varix and decompensation were higher in the high FeNO group. CONCLUSIONS Lung diffusion capacity decreased according to the disease's severity in early cirrhosis, and showed a good correlation with esophageal varices and ascites.
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Affiliation(s)
- Jun Young Jung
- Department of Internal Medicine, Eulji University School of Medicine, Eulji Hospital, Seoul, Korea
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Herzer K, Post F, Canbay A, Gerken G. [Pulmonary affection in advanced liver disease - hepatepulonary syndrome and portopulmonary hypertension]. MEDIZINISCHE KLINIK (MUNICH, GERMANY : 1983) 2010; 105:916-923. [PMID: 21240591 DOI: 10.1007/s00063-010-1157-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2010] [Accepted: 10/25/2010] [Indexed: 05/30/2023]
Abstract
Patients suffering from severe chronic liver disease, in particular cirrhosis, are at risk for pulmonary complications. The leading clinical symptom is shortness of breath, which can accompany the actual disease as indirect effect because of anemia, faint muscles or ascites. On the other hand, dyspnea can have multiple additive causes in case of accompanying cardial or pulmonary disease. The hepatopulmonary syndrome (HPS) and the portopulmonary hypertension (PoPH) belong to the most relevant pulmonary complications in liver cirrhosis. HPS appears to be more common than PoPH and the presence of either entity increases morbidity and mortality in patients with liver disease. The two diseases have to be strictly distinguished, as they have opposed histological and pathophysiological origin. While the HPS is a dilatative pulmonary- vascular disease, the PoPH is a constrictive or obliterative pulmonary-vascular disease in the context of a liver disease or a portal hypertension. Therefore, these diseases are separate entities also when it comes to diagnostics and therapy.
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Affiliation(s)
- Kerstin Herzer
- Zentrum für Innere Medizin, Gastroenterologie und Hepatologie, Essen, Germany.
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Gupta S, Faughnan ME, Lilly L, Hutchison S, Fowler R, Bayoumi AM. Norfloxacin therapy for hepatopulmonary syndrome: a pilot randomized controlled trial. Clin Gastroenterol Hepatol 2010; 8:1095-8. [PMID: 20816858 DOI: 10.1016/j.cgh.2010.08.011] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2010] [Revised: 07/30/2010] [Accepted: 08/20/2010] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The hepatopulmonary syndrome occurs in up to one-third of patients with cirrhosis. Animal models of this disease suggest that endotoxemia might cause nitric oxide-mediated vascular dilatation that can be inhibited by the antibiotic norfloxacin. We sought to test this hypothesis in humans. METHODS We conducted a pilot randomized, controlled crossover trial of norfloxacin 400 mg twice daily for 4 weeks with a 4-week washout period to assess the feasibility of a larger trial. The primary clinical end point was change in alveolar-arterial oxygen gradient (AaDO₂). RESULTS Recruitment was challenging, and change in AaDO₂ was highly variable. We recruited 9 adults (1 woman; age, 60 ± 9 years; AaDO₂, 50 ± 22 mm Hg). AaDO₂ decreased by 0.8 ± 4.8 and 3.4 ± 12.4 mm Hg while on norfloxacin and placebo, respectively (P = .59). CONCLUSIONS Recruitment difficulties and variability of the primary outcome measure suggest the need for a multicenter clinical research network for future therapeutic trials in this disease. There was no major effect of norfloxacin on gas exchange in patients with hepatopulmonary syndrome.
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Affiliation(s)
- Samir Gupta
- Department of Medicine, University of Toronto, Ontario, Canada.
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Respiratory failure and hypoxemia in the cirrhotic patient including hepatopulmonary syndrome. Curr Opin Anaesthesiol 2010; 23:133-8. [PMID: 20019600 DOI: 10.1097/aco.0b013e328335f024] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Liver cirrhosis and portal hypertension present with three unique pulmonary complications that are the subject of ongoing clinical research: hepatopulmonary syndrome, portopulmonary hypertension (POPH), and hepatic hydrothorax. The present article is based on a review of the current literature on how to manage these disorders, which are highly important to both anesthesiologists and intensive care physicians. RECENT FINDINGS Hepatopulmonary syndrome leads to progressive hypoxemia through diffuse vasodilatation of the pulmonary microcirculation. Liver transplantation, although associated with increased mortality, is the only viable treatment. POPH occurs when vascular remodeling triggers an increase in pulmonary artery pressure and resistance. The role of liver transplantation in POPH is controversial given the excessive mortality in patients with moderate to severe POPH. Medical treatment is able to decrease pulmonary artery pressures, though multicenter randomized controlled trials showing improved outcome are lacking to date. Ultrasound plays an increasingly important role in the diagnosis of all three conditions. SUMMARY Patients with end-stage liver disease are at risk for respiratory failure and hypoxemia and need to be screened for hepatopulmonary syndrome, POPH, and hepatic hydrothorax. Failure to timely recognize and adequately treat these complications of cirrhosis may have severe consequences.
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Roberts KE, Kawut SM, Krowka MJ, Brown RS, Trotter JF, Shah V, Peter I, Tighiouart H, Mitra N, Handorf E, Knowles JA, Zacks S, Fallon MB. Genetic risk factors for hepatopulmonary syndrome in patients with advanced liver disease. Gastroenterology 2010; 139:130-9.e24. [PMID: 20346360 PMCID: PMC2908261 DOI: 10.1053/j.gastro.2010.03.044] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2009] [Revised: 02/24/2010] [Accepted: 03/04/2010] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Hepatopulmonary syndrome (HPS) affects 10%-30% of patients with cirrhosis and portal hypertension and significantly increases mortality. Studies in experimental models indicate that pulmonary angiogenesis contributes to the development of HPS, but pathogenesis in humans is poorly understood. We investigated genetic risk factors for HPS in patients with advanced liver disease. METHODS We performed a multicenter case-control study of patients with cirrhosis being evaluated for liver transplantation. Cases had an alveolar-arterial oxygen gradient > or = 15 mm Hg (or > or =20 mm Hg if age > 64 years) and contrast echocardiography with late appearance of microbubbles after venous injection of agitated saline (intrapulmonary vasodilatation); controls did not meet both criteria for case status. The study sample included 59 cases and 126 controls. We genotyped 1086 common single nucleotide polymorphisms (SNPs) in 94 candidate genes. RESULTS Forty-two SNPs in 21 genes were significantly associated with HPS after adjustments for race and smoking. Eight genes had at least 2 SNPs associated with disease: CAV3, ENG, NOX4, ESR2, VWF, RUNX1, COL18A1, and TIE1. For example, rs237872 in CAV3 showed an odds ratio of 2.75 (95% confidence interval: 1.65-4.60, P = .0001) and rs4837192 in ENG showed an odds ratio of 0.35 (95% confidence interval: 0.14-0.89, P = .027). Furthermore, variation in CAV3 and RUNX1 was associated with HPS in gene-based analyses. CONCLUSIONS Polymorphisms in genes involved in the regulation of angiogenesis are associated with the risk of HPS. Further investigation of these biologic pathways might elucidate the mechanisms that mediate the development of HPS in certain patients with severe liver disease.
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Affiliation(s)
- Kari E. Roberts
- Department of Medicine, Tufts Medical Center, Boston, Massachusetts
| | - Steven M. Kawut
- Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania,Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | | | - Robert S. Brown
- Department of Medicine, Columbia University, New York, New York
| | - James F. Trotter
- Department of Medicine, University of Colorado, Denver, Colorado
| | - Vijay Shah
- Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Inga Peter
- Department of Genetic and Genomic Sciences, Mount Sinai School of Medicine, New York, New York
| | - Hocine Tighiouart
- Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts
| | - Nandita Mitra
- Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | - Elizabeth Handorf
- Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | - James A. Knowles
- Department of Psychiatry, University of Southern California, Los Angeles, California
| | - Steven Zacks
- Department of Medicine, University of Southern California, Los Angeles, California
| | - Michael B. Fallon
- Department of Medicine, University of Texas Health Science Center, Houston, Texas
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De Santis M, Rodrigues LV, Matos F. Síndroma hepatopulmonar: Relato de um caso clínico e revisão do tema. REVISTA PORTUGUESA DE PNEUMOLOGIA 2010. [DOI: 10.1016/s0873-2159(15)30062-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Miyamoto A, Katsuta Y, Zhang XJ, Li HL, Ohsuga M, Komeichi H, Shimizu S, Akimoto T, Mizuno K. Effect of chronic methylene blue administration on hypoxemia in rats with common bile duct ligation. Hepatol Res 2010; 40:622-32. [PMID: 20412326 DOI: 10.1111/j.1872-034x.2010.00640.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
AIM Acute administration of methylene blue (MB) can reverse hypoxemia in patients with hepatopulmonary syndrome (HPS). We evaluated the effect of chronic MB administration in common bile duct-ligated rats, which develop HPS by 5 weeks after surgery. METHODS A total of 96 Sprague-Dawley rats were used, including 63 rats with common bile duct ligation (CBDL), 22 sham-operated rats and 11 normal control rats. MB (6 mg/kg) was injected s.c. once a day for 4 weeks. Evaluation of hemodynamics and intrapulmonary vascular dilatation (IPVD), as well as blood sampling for arterial blood gas analysis, were done under conscious and unrestrained conditions. Hemodynamics were assessed by the reference sample method using (141)Ce-microspheres (15 microm in diameter), and IPVD was also determined by i.v. injection of these microspheres. Histological examination of the lungs was done with hematoxylin-eosin staining and immunohistochemical staining for von Willebrand factor or vascular endothelial growth factor. RESULTS Both the arterial oxygen tension and alveolar-arterial oxygen difference were significantly improved in MB-treated CBDL rats. The hyperdynamic circulation and splanchnic hyperemia seen in untreated CBDL rats were also alleviated by MB treatment. However, IPVD was not affected by MB. Histological examination of the lungs indicated that MB treatment reduced the proliferation of alveolar capillary vessels and angiogenesis, leading to improvement of arterial dysoxygenation. Hepatic synthetic and detoxification functions, as well as renal function, were not altered by MB treatment. CONCLUSION Methylene blue may be a candidate treatment for HPS that does not cause deterioration of hepatic or renal function.
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Affiliation(s)
- Akiko Miyamoto
- Division of Cardiology, Hepatology, Geriatrics and Integrated Medicine, Department of Internal Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
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Teles Martins C, Rosal Gonçalves J. [Boundaries of the lung - Relationship to the gastrointestinal system]. REVISTA PORTUGUESA DE PNEUMOLOGIA 2010; 16:133-48. [PMID: 20054513 DOI: 10.1016/s0873-2159(15)30011-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
The relation between the respiratory and gastrointestinal systems has been long recognized and depends on various anatomical, physiological and pathological mechanisms. The certain recognition of some interactions, such as the relation between asthma and gastroesophageal reflux, is more or less intuitive to the pulmonogist, whereas other areas of confluence are more easily missed, such as the relation between airway disorders and inflammatory bowel disease. The purpose of this article is to review the interaction between the lung and the gastrointestinal systems, as far as anatomy, physiology, pathology, clinical manifestations and therapeutical options go.
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Abstract
Advanced liver disease and portal hypertension produce various intrathoracic complications that involve the pleural space, the lung parenchyma, and the pulmonary circulation. Dyspnea and arterial hypoxemia are the most common symptoms and signs in patients with such complications. This article focuses on the diagnosis and management of hepatopulmonary syndrome, portopulmonary hypertension, and hepatic hydrothorax. All are pulmonary processes associated with end-stage liver disease that lead to significant morbidity and affect the quality of life of patients who are suffering from liver cirrhosis.
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Affiliation(s)
- C Singh
- Santa Barbara Cottage Hospital, 675 Central Avenue, Apartment 5, Buellton, CA 93427, USA
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