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Ding F, Yang L, Cao W, Sun J, Shi F, Wang Y, Hu C, Kang W, Han J, Song Q, Ma Y, Jin J. Plasma Reticulocalbin 3 (RCN3) is a Novel Biomarker for the Early Diagnosis of Hepatopulmonary Syndrome in Cirrhotic Patients. Lung 2025; 203:50. [PMID: 40111510 DOI: 10.1007/s00408-025-00807-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 03/12/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND Hepatopulmonary syndrome (HPS) is a severe complication in cirrhotic patients and characterized by abnormal intrapulmonary vasodilation (IPVD), resulting in impaired oxygenation. Recent studies highlight the pivotal role and clinical merit of Reticulocalbin 3 (RCN3) in interstitial pulmonary remodeling. OBJECTIVES This study aimed to investigate the clinical value of plasma RCN3 for early diagnosis of HPS in cirrhotic patients. METHODS This prospective observational study on a cohort including 41 healthy control subjects and 247 cirrhotic patients with/without HPS, in which most HPS occurs in the mild stage. Plasma levels of RCN3 and key HPS-associated vasoactive factors are compared between patients with and without HPS/IPVD. The predictive value of RCN3 for the diagnosis of HPS is further analyzed. RESULTS Patients with HPS had a severe condition. Plasma RCN3 was decreased in cirrhotic patients versus health control, but it is significantly higher in patients with HPS/IPVD than without non-HPS/IPVD. Notably, RCN3 level is positively correlated with P(A-a)O2 and MELD scores as well as plasma levels of angiogenetic factors VEGF and AngII. Although the plasma levels of vasoactive factors were significantly different between HPS and non-HPS patients, only plasma RCN3 and albumin are independently associated with HPS in cirrhotic patients. Plasma RCN3 exhibits better predictive value in HPS diagnosis (RCN3, AUC = 0.657, 95% CI 0.571-0.744, p < 0.001). Interestingly, the combination of RCN3 and albumin achieves more efficiency in HPS prediction (AUC = 0.711, 95% CI 0.630-0.792, p < 0.0001). CONCLUSIONS Circulating RCN3 is likely a relatively specific earlier biomarker for the prediction of early or latent HPS in cirrhotic patients, and the combination of RCN3-ALB can achieve more efficiency in HPS prediction.
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Affiliation(s)
- Fangping Ding
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No.8 Xi Tou Tiao, Youanmen Wai, Beijing, China
| | - Liu Yang
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No.8 Xi Tou Tiao, Youanmen Wai, Beijing, China
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, N0.5 Jingyuan Road, Beijing, China
| | - Wenhui Cao
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No.8 Xi Tou Tiao, Youanmen Wai, Beijing, China
| | - Jie Sun
- Department of Respiratory and Critical Care Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Fengwei Shi
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No.8 Xi Tou Tiao, Youanmen Wai, Beijing, China
| | - Yingfei Wang
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No.8 Xi Tou Tiao, Youanmen Wai, Beijing, China
| | - Caixia Hu
- Hepatic Disease and Tumor Interventional Treatment Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Weiwei Kang
- Fourth Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Jing Han
- Ultrasound and Functional Diagnosis Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Qingkun Song
- Department of Clinical Epidemiology, Department of Center of Biobank, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yingmin Ma
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No.8 Xi Tou Tiao, Youanmen Wai, Beijing, China.
| | - Jiawei Jin
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, N0.5 Jingyuan Road, Beijing, China.
- The Clinical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
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Zaka AZ, Mangoura SA, Ahmed MA. New updates on hepatopulmonary syndrome: A comprehensive review. Respir Med 2025; 236:107911. [PMID: 39662637 DOI: 10.1016/j.rmed.2024.107911] [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: 09/12/2024] [Revised: 11/28/2024] [Accepted: 12/08/2024] [Indexed: 12/13/2024]
Abstract
Hepatopulmonary syndrome (HPS) is a serious pulmonary vascular complication that causes arterial hypoxemia in the setting of liver disease. HPS has a progressive course and is associated with a two-fold increased risk of mortality relative to cirrhotic patients without HPS. It primarily affects patients with portal hypertension. The key pathological features of HPS include intrapulmonary angiogenesis and vascular dilations (IPVDs). The prevalence of HPS varies widely due to inconsistent diagnostic criteria and a lack of standardized protocols. Despite advances in understanding its pathophysiology, no effective curative treatments for HPS exist. Liver transplantation remains the only definitive treatment, improving survival and altering the disease natural course. This review explores the pathophysiology, clinical features, and therapeutic strategies for HPS, highlighting recent advances in the literature.
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Affiliation(s)
- Andrew Z Zaka
- Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt.
| | - Safwat A Mangoura
- Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo, 11829, Egypt.
| | - Marwa A Ahmed
- Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt
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Gu J, Guo Y, Wu B, He J. Liver injury associated with endothelin receptor antagonists: a pharmacovigilance study based on FDA adverse event reporting system data. Int J Clin Pharm 2024; 46:1307-1316. [PMID: 38902469 DOI: 10.1007/s11096-024-01757-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 05/17/2024] [Indexed: 06/22/2024]
Abstract
BACKGROUND Endothelin receptor antagonists are commonly used in clinical practice, with concerns about their hepatotoxicity. AIM This study aimed to conduct a comprehensive pharmacovigilance study based on FDA adverse event reporting system data to evaluate the possible association between endothelin receptor antagonists and drug-induced liver injury. METHOD Adverse event reports from FDA adverse event reporting system between January 2004 and December 2022 were analyzed. Disproportionality algorithms, including reporting odds ratio and information component, were used to evaluate the association between endothelin receptor antagonists and liver injury. Sex- and age-stratified analyses of drug-induced liver injury events were also conducted in relation to endothelin receptor antagonists. RESULTS Significant associations between bosentan, macitentan, and liver injury were identified. Bosentan showed a strong link with liver injury, with reporting odds ratios for cholestatic injury at 7.59 (95% confidence interval: 6.90-8.35), hepatocellular injury at 5.63 (5.29-6.00), and serious drug-related hepatic disorders events at 1.33 (1.24-1.43). Drug-induced liver injury signals associated with bosentan were detected in all age groups. Macitentan was associated with liver injury, with reporting odds ratios for hepatic failure at 1.64 (1.39-1.94), cholestatic injury at 1.62 (1.43-1.83), and serious drug-related hepatic disorders events at 1.40 (1.29-1.51). No drug-induced liver injury signal was detected for ambrisentan, and no significant sex differences were observed in drug-induced liver injury events. CONCLUSION Both bosentan and macitentan are associated with liver injury. Routine monitoring of serum aminotransferase levels is recommended, especially in patients at higher risk of liver injury. Further research into drug-drug interactions involving endothelin receptor antagonists is warranted.
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Affiliation(s)
- Jinjian Gu
- West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China
| | - Yuting Guo
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Bin Wu
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jinhan He
- West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China.
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Verstraeten M, Lefere S, Raevens S. Pulmonary vascular complications of cirrhosis: hepatopulmonary syndrome and portopulmonary hypertension. Acta Clin Belg 2024; 79:384-391. [PMID: 39873530 DOI: 10.1080/17843286.2025.2456697] [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: 12/20/2024] [Accepted: 01/13/2025] [Indexed: 01/30/2025]
Abstract
Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH) are two distinct pulmonary vascular complications seen in patients with liver disease and/or portal hypertension. HPS is characterized by disturbed gas exchange and hypoxemia because of intrapulmonary vascular dilatations. POPH is defined by pulmonary arterial hypertension, which might lead to right heart failure. HPS affects up to 30% of patients with end-stage liver disease requiring liver transplantation. POPH is rarer and affects 1-5% of this patient population. If not recognized and left untreated, these disorders result in significant mortality. This review provides an update on HPS and POPH and discusses their clinical characteristics, screening and diagnostic modalities, and management, including the place of liver transplantation.
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Affiliation(s)
- Maïté Verstraeten
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center, Ghent University, Ghent, Belgium
| | - Sander Lefere
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center, Ghent University, Ghent, Belgium
| | - Sarah Raevens
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center, Ghent University, Ghent, Belgium
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Dandavate V, Bolshette N, Van Drunen R, Manella G, Bueno-Levy H, Zerbib M, Kawano I, Golik M, Adamovich Y, Asher G. Hepatic BMAL1 and HIF1α regulate a time-dependent hypoxic response and prevent hepatopulmonary-like syndrome. Cell Metab 2024; 36:2038-2053.e5. [PMID: 39106859 DOI: 10.1016/j.cmet.2024.07.003] [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: 01/29/2024] [Revised: 05/28/2024] [Accepted: 07/05/2024] [Indexed: 08/09/2024]
Abstract
The transcriptional response to hypoxia is temporally regulated, yet the molecular underpinnings and physiological implications are unknown. We examined the roles of hepatic Bmal1 and Hif1α in the circadian response to hypoxia in mice. We found that the majority of the transcriptional response to hypoxia is dependent on either Bmal1 or Hif1α, through shared and distinct roles that are daytime determined. We further show that hypoxia-inducible factor (HIF)1α accumulation upon hypoxia is temporally regulated and Bmal1 dependent. Unexpectedly, mice lacking both hepatic Bmal1 and Hif1α are hypoxemic and exhibit increased mortality upon hypoxic exposure in a daytime-dependent manner. These mice display mild liver dysfunction with pulmonary vasodilation likely due to extracellular signaling regulated kinase (ERK) activation, endothelial nitric oxide synthase, and nitric oxide accumulation in lungs, suggestive of hepatopulmonary syndrome. Our findings indicate that hepatic BMAL1 and HIF1α are key time-dependent regulators of the hypoxic response and can provide molecular insights into the pathophysiology of hepatopulmonary syndrome.
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Affiliation(s)
- Vaishnavi Dandavate
- Department of Biomolecular Sciences, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Nityanand Bolshette
- Department of Biomolecular Sciences, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Rachel Van Drunen
- Department of Biomolecular Sciences, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Gal Manella
- Department of Biomolecular Sciences, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Hanna Bueno-Levy
- Department of the Veterinary Resources, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Mirie Zerbib
- Department of the Veterinary Resources, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Ippei Kawano
- Department of Biomolecular Sciences, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Marina Golik
- Department of Biomolecular Sciences, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Yaarit Adamovich
- Department of Biomolecular Sciences, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Gad Asher
- Department of Biomolecular Sciences, Weizmann Institute of Science, 7610001 Rehovot, Israel.
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Mangoura SA, Ahmed MA, Hamad N, Zaka AZ, Khalaf KA, Mahdy MA. Vildagliptin ameliorates intrapulmonary vasodilatation and angiogenesis in chronic common bile duct ligation-induced hepatopulmonary syndrome in rat. Clin Res Hepatol Gastroenterol 2024; 48:102408. [PMID: 38925324 DOI: 10.1016/j.clinre.2024.102408] [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: 04/04/2024] [Revised: 06/16/2024] [Accepted: 06/23/2024] [Indexed: 06/28/2024]
Abstract
INTRODUCTION Experimental hepatopulmonary syndrome (HPS) is best reproduced in the rat common bile duct ligation (CBDL) model. Vildagliptin (Vild) is an anti-hyperglycemic drug that exerts beneficial anti-inflammatory, anti-oxidant and anti-fibrotic effects. Therefore, the present search aimed to explore the possible effectiveness of Vild in CBDL-induced HPS model. METHODS Four groups of male Wistar rats which weigh 220-270 g were used, including the normal control group, the sham control group, the CBDL group and CBDL+Vild group. The first three groups received i.p. saline, while the last group was treated with i.p. Vild (10 mg/kg/day) from the 15th to 28th day of the experiment. RESULTS CBDL decreased the survivability and body weight of rats, increased diameter of the pulmonary vessels, and altered the arterial blood gases and the liver function parameters. Additionally, it increased the pulmonary expressions of endothelin-1 (ET-1) and tumor necrosis factor-α (TNF-α) mRNA as well as endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor-A (VEGF-A) proteins. The CBDL rats also exhibited elevation of the pulmonary interleukin-6 (IL-6), dipeptidyl peptidase-4 (DPP-4) and nitric oxide (NO) levels along with reduction of the pulmonary total anti-oxidant capacity and glucagon-like peptide-1 (GLP-1) levels. Vild mitigated these alterations and improved the histopathological abnormalities caused by CBDL. CONCLUSION Vild effectively attenuated CBDL-induced HPS through its anti-oxidant and anti-inflammatory effects along with its modulatory effects on ET-1/NOS/NO and TNF-α/IL-6/VEGF-A signaling implicated in the regulation of intrapulmonary vasodilatation and angiogenesis, respectively.
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Affiliation(s)
- Safwat A Mangoura
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt; Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Marwa A Ahmed
- Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Nashwa Hamad
- Department of Pathology and Clinical Pathology, Faculty of Veterinary Medicine, Assiut University, Assiut 71515, Egypt
| | - Andrew Z Zaka
- Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt.
| | - Khaled A Khalaf
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
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Chooklin S, Chuklin S, Posivnych M, Krystopchuk S. Pathophysiological basis of hepatopulmonary syndrome. Gastroenterology 2024; 58:73-81. [DOI: 10.22141/2308-2097.58.1.2024.590] [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] [Indexed: 07/02/2024]
Abstract
Circulatory changes with increased blood flow and vasodilatation/vasoconstriction imbalance are an integral consequence of liver cirrhosis and portal hypertension and can affect the pulmonary circulation with the development of vascular disorders, with hepatopulmonary syndrome (HPS) being the most common. HPS is a serious pulmonary complication of progressive liver disease, resulting in a poor clinical prognosis. Vascular tone decrease, monocytic infiltration of pulmonary vessels, formation of intrapulmonary arteriovenous shunts, dysfunction of alveolar type II cells, destruction of the endothelial glycocalyx are important in the pathogenesis of HPS. Abnormalities of pulmonary capillaries lead to hypoxemia caused by a violation of the ventilation/perfusion ratio, diffusion disorders, and the development of arteriovenous anastomoses. Infiltration of the pulmonary vessels by monocytes is one of the key factors of HPS. This migration is facilitated by the intestinal microbiota translocation into the portal bloodstream with increased expression of proinflammatory cytokines (tumor necrosis factor α, interleukins 1, 6), leading to the activation of monocytes. Monocytes located in the pulmonary circulation promote the vasodilation through the activation of inducible nitric oxide (NO) synthase and thus NO production. This is also associated with endothelial dysfunction due to a decreased hepatic secretion of bone morphogenetic protein 9 and increased endothelin 1, endothelial overexpression of endothelin B receptors, and increased endothelial NO production. Proangiogenic factors such as vascular endothelial growth factor, platelet-derived growth factor, and placental growth factor play an important role in the proliferation of pulmonary capillaries. Circulation of tumor necrosis factor α, bile acids and monocyte infiltration in the pulmonary circulation lead to increased apoptosis of alveolar type II cells and decreased surfactant synthesis. Chronic inflammation in HPS disrupts the continuity of the endothelial glycocalyx layer. This article provides an overview of the current knowledge on the pathogenesis of HPS, summarizes many features of the disease based on the literature research in MEDLINE database on the PubMed platform.
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Zhang Y, Fang XM. The pan-liver network theory: From traditional chinese medicine to western medicine. CHINESE J PHYSIOL 2023; 66:401-436. [PMID: 38149555 DOI: 10.4103/cjop.cjop-d-22-00131] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2023] Open
Abstract
In traditional Chinese medicine (TCM), the liver is the "general organ" that is responsible for governing/maintaining the free flow of qi over the entire body and storing blood. According to the classic five elements theory, zang-xiang theory, yin-yang theory, meridians and collaterals theory, and the five-viscera correlation theory, the liver has essential relationships with many extrahepatic organs or tissues, such as the mother-child relationships between the liver and the heart, and the yin-yang and exterior-interior relationships between the liver and the gallbladder. The influences of the liver to the extrahepatic organs or tissues have been well-established when treating the extrahepatic diseases from the perspective of modulating the liver by using the ancient classic prescriptions of TCM and the acupuncture and moxibustion. In modern medicine, as the largest solid organ in the human body, the liver has the typical functions of filtration and storage of blood; metabolism of carbohydrates, fats, proteins, hormones, and foreign chemicals; formation of bile; storage of vitamins and iron; and formation of coagulation factors. The liver also has essential endocrine function, and acts as an immunological organ due to containing the resident immune cells. In the perspective of modern human anatomy, physiology, and pathophysiology, the liver has the organ interactions with the extrahepatic organs or tissues, for example, the gut, pancreas, adipose, skeletal muscle, heart, lung, kidney, brain, spleen, eyes, skin, bone, and sexual organs, through the circulation (including hemodynamics, redox signals, hepatokines, metabolites, and the translocation of microbiota or its products, such as endotoxins), the neural signals, or other forms of pathogenic factors, under normal or diseases status. The organ interactions centered on the liver not only influence the homeostasis of these indicated organs or tissues, but also contribute to the pathogenesis of cardiometabolic diseases (including obesity, type 2 diabetes mellitus, metabolic [dysfunction]-associated fatty liver diseases, and cardio-cerebrovascular diseases), pulmonary diseases, hyperuricemia and gout, chronic kidney disease, and male and female sexual dysfunction. Therefore, based on TCM and modern medicine, the liver has the bidirectional interaction with the extrahepatic organ or tissue, and this established bidirectional interaction system may further interact with another one or more extrahepatic organs/tissues, thus depicting a complex "pan-hepatic network" model. The pan-hepatic network acts as one of the essential mechanisms of homeostasis and the pathogenesis of diseases.
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Affiliation(s)
- Yaxing Zhang
- Department of Physiology; Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong; Issue 12th of Guangxi Apprenticeship Education of Traditional Chinese Medicine (Shi-Cheng Class of Guangxi University of Chinese Medicine), College of Continuing Education, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Xian-Ming Fang
- Department of Cardiology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine (Guangxi Hospital of Integrated Chinese Medicine and Western Medicine, Ruikang Clinical Faculty of Guangxi University of Chinese Medicine), Guangxi University of Chinese Medicine, Nanning, Guangxi, China
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Cho J, Johnson BD, Watt KD, Niven AS, Shin J, Kim CH. Alterations in Pulmonary Vasomotor Modulators Post Aerobic Exercise Training in Non-Alcoholic Fatty Liver Disease. Respir Physiol Neurobiol 2023:104089. [PMID: 37269888 DOI: 10.1016/j.resp.2023.104089] [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: 04/06/2023] [Revised: 05/18/2023] [Accepted: 05/31/2023] [Indexed: 06/05/2023]
Abstract
This study investigated the impact of exercise training on major pulmonary vasomotor mediators and receptors including endothelial nitric oxide synthase (eNOS) inducible NOS (iNOS), endothelin-1 (ET-1), ET-1 receptors A (ETA) and-B (ETB) in high-fat-high-carbohydrate (HFHC) induced non-alcoholic fatty liver disease (NAFLD). NAFLD increased iNOS, ET-1 and ETA (p<0.05), but not ETB (p>0.05). Exercise attenuated iNOS, ET-1 and ETA (p<0.05)., but not ETB (p>0.05) and eNOS (p>0.05). Exercise training is beneficial for pulmonary vasculature in NAFLD. DATA AVAILABILITY: The data analyzed in the present study will be available from the corresponding author upon reasonable request.
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Affiliation(s)
- Jinkyung Cho
- Department of Cardiovascular Disease, Mayo Clinic, Rochester, MN
| | - Bruce D Johnson
- Department of Cardiovascular Disease, Mayo Clinic, Rochester, MN
| | - Kymberly D Watt
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Alexander S Niven
- Department of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN
| | - Junchul Shin
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH
| | - Chul-Ho Kim
- Department of Cardiovascular Disease, Mayo Clinic, Rochester, MN.
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Nassef NAA, Abd-El Hamid MS, Abusikkien SA, Ahmed AI. Quercetin ameliorates acute lung injury in a rat model of hepatopulmonary syndrome. BMC Complement Med Ther 2022; 22:320. [PMID: 36463144 PMCID: PMC9719635 DOI: 10.1186/s12906-022-03785-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 11/09/2022] [Indexed: 12/07/2022] Open
Abstract
BACKGROUND Common bile duct ligation (BDL) is a rat experimental model to induce biliary cirrhosis. Lung fibrosis and pulmonary vascular angiogenesis and congestion are the most common complications of biliary cirrhosis that is known as hepatopulmonary syndrome. The aim of the present work is to investigate the acute lung injury in a BDL model and to investigate the possible protective effect of quercetin on this injury. METHODS Twenty-four adult male albino rats of the Wister strain (weighing 150-250 g). Animals were divided into 3 groups, with 8 rats each: Group I: Sham-operated group (control). Group II: Bile duct ligation group (BDL) sacrificed after 28 days from the surgery. Group III: Quercetin-treated bile duct ligation group (Q-BDL) was given orally by gastric gavage in a dose of 50 mg/kg/day, starting from the 4th day of the operation until the 28th day. At the end of the experiment, at day 28, all rats were sacrificed. Lung specimens were processed to measure Endothelin B receptor gene expression by PCR, lung surfactant by ELISA, "eNO" s by immunohistochemistry. Histological assessment was done using; H&E, Masson's trichrome, PAS, toluidine blue-stained semi-thin sections, transmission electron microscope. Histomorphometric and statistical studies were done. RESULTS BDL group showed significant increase in lung index together with mononuclear cellular infiltration denoting lung inflammatory state. Also, the significant increase in pulmonary endothelial nitric oxide synthase ("eNO" s) area percent and endothelin B receptor (ETB) gene expression indicates enhanced angiogenesis. Pulmonary surfactant concentration was significantly decreased together with thickening of interalveolar septa denoting lung injury and fibrosis. Quercetin led to significant decrease in lung index, pulmonary "eNO" s area percent, ETB gene expression and significant increase in pulmonary surfactant concentration. Quercetin treatment improved histological changes and morphometric measurements, limited mononuclear cellular infiltration and decreased perivascular and perialveolar collagen deposition. CONCLUSION Quercetin ameliorates the hepatopulmonary syndrome-induced lung injury through its anti-inflammatory, antioxidative and antifibrotic effects.
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Affiliation(s)
- Noha Abdel-Aziz Nassef
- grid.7269.a0000 0004 0621 1570Assistant Professor of Physiology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Manal S. Abd-El Hamid
- grid.7269.a0000 0004 0621 1570Assistant Professor of Physiology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Samy A. Abusikkien
- grid.7269.a0000 0004 0621 1570Lecturer of Anatomy, Rabigh Faculty of Medicine, King Abdulaziz University, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Asmaa Ibrahim Ahmed
- grid.7269.a0000 0004 0621 1570Assistant Professor of Anatomy, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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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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13
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Yi Z, Zhang M, Ma Z, Tuo B, Liu A, Deng Z, Zhao Y, Li T, Liu X. Role of the posterior mucosal defense barrier in portal hypertensive gastropathy. Biomed Pharmacother 2021; 144:112258. [PMID: 34614465 DOI: 10.1016/j.biopha.2021.112258] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/24/2021] [Accepted: 09/26/2021] [Indexed: 12/15/2022] Open
Abstract
Portal hypertensive gastropathy (PHG) is a complication of cirrhotic or noncirrhotic portal hypertension. PHG is very important in the clinic because it can cause acute or even massive blood loss, and its treatment efficacy and prognosis are poor. Currently, the incidence of PHG in patients with cirrhosis is 20-80%, but its pathogenesis is complicated and poorly understood. Studies have shown that portal hypertension can cause changes in gastric mucosal microcirculation hemodynamics, leading to changes in gastric mucosal histology and function and thereby weakening the mucosal defense barrier. However, no specific drug treatment plans are currently available. This article reviews the current literature to further our understanding of the mechanism underlying PHG and the relationship between PHG and the posterior mucosal defense barrier and to explore new therapeutic targets.
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Affiliation(s)
- Zhiqiang Yi
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China; Department of Gastroenterology, Fuling Central Hospital of Chongqing City, Chongqing, China
| | - Minglin Zhang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Zhiyuan Ma
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China; Digestive Disease Institute of Guizhou Province, Zunyi, Guizhou Province, China; Department of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Biguang Tuo
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China; Digestive Disease Institute of Guizhou Province, Zunyi, Guizhou Province, China
| | - Aimin Liu
- Department of Gastroenterology, Fuling Central Hospital of Chongqing City, Chongqing, China
| | - Zilin Deng
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Yingying Zhao
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Taolang Li
- Department of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China.
| | - Xuemei Liu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China; Digestive Disease Institute of Guizhou Province, Zunyi, Guizhou Province, China.
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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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Benz F, Mohr R, Tacke F, Roderburg C. Pulmonary Complications in Patients with Liver Cirrhosis. J Transl Int Med 2020; 8:150-158. [PMID: 33062591 PMCID: PMC7534492 DOI: 10.2478/jtim-2020-0024] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Patients with advanced chronic liver diseases, particularly with decompensated liver cirrhosis, can develop specific pulmonary complications independently of any pre-existing lung disease. Especially when dyspnea occurs in combination with liver cirrhosis, patients should be evaluated for hepato-pulmonary syndrome (HPS), porto-pulmonary hypertension (PPHT), hepatic hydrothorax and spontaneous bacterial empyema, which represent the clinically most relevant pulmonary complications of liver cirrhosis. Importantly, the pathophysiology, clinical features, diagnosis and the corresponding therapeutic options differ between these entities, highlighting the role of specific diagnostics in patients with liver cirrhosis who present with dyspnea. Liver transplantation may offer a curative therapy, including selected cases of HPS and PPHT. In this review article, we summarize the pathogenesis, clinical features, diagnostic algorithms and treatment options of the 4 specific pulmonary complications in patients with liver cirrhosis.
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Affiliation(s)
- Fabian Benz
- Charité University Medicine Berlin, Department of Hepatology & Gastroenterology, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Raphael Mohr
- Charité University Medicine Berlin, Department of Hepatology & Gastroenterology, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Frank Tacke
- Charité University Medicine Berlin, Department of Hepatology & Gastroenterology, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Christoph Roderburg
- Charité University Medicine Berlin, Department of Hepatology & Gastroenterology, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
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Roles of Endothelin B Receptors and Endothelial Nitric Oxide Synthase in the Regulation of Pulmonary Hemodynamic in Cirrhotic Rats. J Cardiovasc Pharmacol 2020; 73:178-185. [PMID: 30839511 DOI: 10.1097/fjc.0000000000000650] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Hepatopulmonary syndrome and portopulmonary hypertension are common complications of liver disorders. This study aimed to determine roles of ET-B receptors and endothelial-derived NO synthase in the regulation of pulmonary hemodynamic in cirrhotic rats. METHODS Male Sprague-Dawley rats were divided into the Sham and common bile duct ligation (CBDL) groups. After 28 days, animals were anesthetized, and the right ventricle, femoral artery, and vein cannulated. Then, intravenous injection of BQ-788 (a selective ET-B receptor antagonist) and L-NAME (eNOS inhibitor) were performed sequentially. RESULTS After the first injection of BQ-788, the right ventricular systolic pressure (RVSP) and mean arterial systemic pressure increased only in the Sham group. L-NAME increased RVSP in the Sham and CBDL groups, whereas mean arterial systemic pressure elevated only in the Sham group significantly. Reinjection of BQ-788 increased RVSP in the Sham group, whereas it decreased RVSP in the CBDL group. Both plasma NO metabolites and lung endothelin-1 increased in the CBDL group. CONCLUSION ET-B receptors on the endothelial cells play roles in the regulation of pulmonary and systemic vascular tone in normal condition through the NO-mediated pathway, whereas ET-B receptors on the smooth muscle cells have a role in the pulmonary vascular tone in liver cirrhosis.
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Bakr AG, El-Bahrawy AH, Taha HH, Ali FEM. Diosmin enhances the anti-angiogenic activity of sildenafil and pentoxifylline against hepatopulmonary syndrome via regulation of TNF-α/VEGF, IGF-1/PI3K/AKT, and FGF-1/ANG-2 signaling pathways. Eur J Pharmacol 2020; 873:173008. [PMID: 32050083 DOI: 10.1016/j.ejphar.2020.173008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 02/06/2020] [Accepted: 02/07/2020] [Indexed: 02/08/2023]
Abstract
Hepatopulmonary syndrome (HPS) is a severe complication of hepatic cirrhosis, which is characterized by hypoxia, intrapulmonary vasodilation, inflammation, and angiogenesis. In this study, we aimed to investigate the regulatory effects of diosmin (DS) on selected phosphodiesterase inhibitors against chronic bile duct ligation (CBDL)-induced HPS. Experimentally, Wistar Albino rats were used and HPS was induced by CBDL for 28 days. DS (100 mg/kg, daily, P.O.), sildenafil (Sild; 10 mg/kg, twice daily, P.O.), and pentoxifylline (PTX; 50 mg/kg, daily, P.O.) were evaluated either alone or in combinations for their anti-angiogenic activity. CBDL significantly altered oxidative stress biomarkers and up-regulated pulmonary mRNA expressions of VEGF, IGF-1, ET-1, iNOS, eNOS, and ANG-2 as well as the protein expressions of vWF, FGF-1, PI3K, AKT, p-AKT, TGF-β, HYP, MPO activity and circulating TNF-α. Treatment with DS, Sild, PTX, and their combinations significantly attenuated molecular and cellular changes due to CBDL. Improvement of histopathological changes was also observed after drug treatment which further supported our results. Furthermore, DS combination with Sild or PTX exhibited an improvement in HPS in comparison to each drug alone. Collectively, DS can augment the anti-angiogenic activity of Sild and PTX during HPS through regulation of TNF-α/VEGF, IGF-1/PI3K/AKT, and FGF-1/ANG-2 signaling pathways.
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Affiliation(s)
- Adel G Bakr
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
| | - Ali H El-Bahrawy
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
| | - Hesham H Taha
- Department of Biochemistry, Faculty of Pharmacy, Al Azhar University, Assiut, 71524, Egypt
| | - Fares E M Ali
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt.
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Soulaidopoulos S, Goulis I, Cholongitas E. Pulmonary manifestations of chronic liver disease: a comprehensive review. Ann Gastroenterol 2020; 33:237-249. [PMID: 32382226 PMCID: PMC7196609 DOI: 10.20524/aog.2020.0474] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 12/06/2019] [Indexed: 12/14/2022] Open
Abstract
Hepatopulmonary syndrome (HPS) and porto-pulmonary hypertension (PoPH) represent relatively common pulmonary vascular complications of advanced liver disease. Despite distinct differences in their pathogenetic background, both clinical states are characterized by impaired arterial oxygenation and limited functional status, and are associated with increased pre-transplantation mortality. Accumulation of ascitic fluid in the pleural cavity, known as hepatic hydrothorax (HH), is another frequent manifestation of decompensated cirrhosis, which may cause severe respiratory dysfunction, depending on the volume of the effusion, the rapidity of its development and its resistance to therapeutic measures. Orthotopic liver transplantation constitutes the only effective treatment able to resolve the pulmonary complications of liver disease. A prioritization policy for liver transplantation has evolved over the past years regarding advanced stages of HPS, yielding favorable outcomes regarding post-transplantation survival and HPS resolution. In contrast, severe PoPH is associated with poor post-transplantation survival. Hence, liver transplantation is recommended only for patients with PoPH and an acceptable reduction in pulmonary pressure values, after receiving PoPH-targeted vasodilating therapy. This review focuses on basic pathogenetic and diagnostic principles and discusses the current therapeutic approaches regarding HPS, PoPH, and HH.
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Affiliation(s)
- Stergios Soulaidopoulos
- First Department of Cardiology, Hippokration General Hospital, National and Kapodistrian University of Athens (Stergios Soulaidopoulos)
| | - Ioannis Goulis
- Fourth Department of Internal Medicine, Hippokration General Hospital, Medical School of Aristotle University of Thessaloniki (Ioannis Goulis)
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens (Evangelos Cholongitas), Greece
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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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20
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Abstract
The most common pulmonary complications of chronic liver disease are hepatic hydrothorax, hepatopulmonary syndrome, and portopulmonary hypertension. Hepatic hydrothorax is a transudative pleural effusion in a patient with cirrhosis and no evidence of underlying cardiopulmonary disease. Hepatic hydrothorax develops owing to the movement of ascitic fluid into the pleural space. Hepatopulmonary syndrome and portopulmonary hypertension are pathologically linked by the presence of portal hypertension; however, their pathophysiologic mechanisms are significantly different. Hepatopulmonary syndrome is characterized by low pulmonary vascular resistance secondary to intrapulmonary vascular dilatations and hypoxemia; portopulmonary hypertension features elevated pulmonary vascular resistance and constriction/obstruction within the pulmonary vasculature.
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Affiliation(s)
- Rodrigo Cartin-Ceba
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA.
| | - Michael J Krowka
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic Rochester, 200 1st Street SW, Rochester, MN 55905, USA
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21
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Does Biliodigestive Anastomosis Have Any Effect on the Reversal of Hepatopulmonary Syndrome in a Biliary Cirrhosis Experimental Model? Dig Dis Sci 2019; 64:3192-3202. [PMID: 31076984 DOI: 10.1007/s10620-019-05658-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 05/03/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND Biliary cirrhosis is associated with hepatopulmonary syndrome (HPS), which is related to increased posttransplant morbidity and mortality. AIMS This study aims to analyze the pathophysiology of biliary cirrhosis and the onset of HPS. METHODS Twenty-one-day-old Wistar rats were subjected to common bile duct ligation and were allocated to two groups: group A (killed 2, 3, 4, 5, or 6 weeks after biliary obstruction) and group B (subjected to biliodigestive anastomosis 2, 3, 4, 5, or 6 weeks after the first procedure and killed 3 weeks later). At the killing, arterial blood was collected for the analyses, and samples from the liver and lungs were collected for histologic and molecular analyses. The gasometric parameters as well as the expression levels of ET-1, eNOS, and NOS genes in the lung tissue were evaluated. RESULTS From a total of 42 blood samples, 15 showed hypoxemia (pO2 < 85 mmHg) and 17 showed an increased oxygen gradient [p (A-a) O2 > 18 mmHg]. The liver histology revealed increased ductular proliferation after common bile duct ligation, and reconstruction of bile flow promoted decreased ductular proliferation 5 and 6 weeks post-common bile duct ligation. Pulmonary alterations consisted of decreased parenchymal airspace and increased medial wall thickness. Biliary desobstruction promoted transitory improvements 5 weeks after biliary obstruction (increased parenchymal airspace and decreased MWT-p = 0.003 and p = 0.004, respectively) as well as increased endothelin expression levels (p = 0.009). CONCLUSIONS The present model showed lung tissue alterations promoted by biliary obstruction. The biliodigestive anastomosis had no clear direct effects on these alterations.
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22
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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: 39] [Impact Index Per Article: 5.6] [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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23
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Angeli P, Bernardi M, Villanueva C, Francoz C, Mookerjee RP, Trebicka J, Krag A, Laleman W, Gines P. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018; 69:406-460. [PMID: 29653741 DOI: 10.1016/j.jhep.2018.03.024] [Citation(s) in RCA: 1737] [Impact Index Per Article: 248.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 03/28/2018] [Indexed: 02/06/2023]
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24
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Raevens S, Geerts A, Paridaens A, Lefere S, Verhelst X, Hoorens A, Van Dorpe J, Maes T, Bracke KR, Casteleyn C, Jonckx B, Horvatits T, Fuhrmann V, Van Vlierberghe H, Van Steenkiste C, Devisscher L, Colle I. Placental growth factor inhibition targets pulmonary angiogenesis and represents a therapy for hepatopulmonary syndrome in mice. Hepatology 2018; 68:634-651. [PMID: 29023811 DOI: 10.1002/hep.29579] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 08/27/2017] [Accepted: 10/02/2017] [Indexed: 12/30/2022]
Abstract
UNLABELLED Hepatopulmonary syndrome (HPS) is a severe complication of cirrhosis with increased risk of mortality. Pulmonary microvascular alterations are key features of HPS; but underlying mechanisms are incompletely understood, and studies on HPS are limited to rats. Placental growth factor (PlGF), a proangiogenic molecule that is selectively involved in pathological angiogenesis, may play an important role in HPS development; however, its role has never been investigated. In this study, we validated an HPS model by common bile duct ligation (CBDL) in mice, investigated the kinetic changes in pulmonary angiogenesis and inflammation during HPS development, and provide evidence for a novel therapeutic strategy by targeting pathological angiogenesis. Mice with CBDL developed hypoxemia and intrapulmonary shunting on a background of liver fibrosis. Pulmonary alterations included increased levels of proangiogenic and inflammatory markers, which was confirmed in serum of human HPS patients. Increased PlGF production in HPS mice originated from alveolar type II cells and lung macrophages, as demonstrated by immunofluorescent staining. Dysfunctional vessel formation in CBDL mice was visualized by microscopy on vascular corrosion casts. Both prophylactic and therapeutic anti-PlGF (αPlGF) antibody treatment impeded HPS development, as demonstrated by significantly less intrapulmonary shunting and improved gas exchange. αPlGF treatment decreased endothelial cell dysfunction in vivo and in vitro and was accompanied by reduced pulmonary inflammation. Importantly, αPlGF therapy did not affect liver alterations, supporting αPlGF's ability to directly target the pulmonary compartment. CONCLUSION CBDL in mice induces HPS, which is mediated by PlGF production; αPlGF treatment improves experimental HPS by counteracting pulmonary angiogenesis and might be an attractive therapeutic strategy for human HPS. (Hepatology 2017).
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Affiliation(s)
- Sarah Raevens
- Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent University Hospital, Ghent, Belgium
| | - Anja Geerts
- Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent University Hospital, Ghent, Belgium
| | - Annelies Paridaens
- Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent University Hospital, Ghent, Belgium
| | - Sander Lefere
- Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent University Hospital, Ghent, Belgium
| | - Xavier Verhelst
- Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent University Hospital, Ghent, Belgium
| | - Anne Hoorens
- Department of Pathology, Ghent University and Ghent University Hospital, Ghent, Belgium
| | - Jo Van Dorpe
- Department of Pathology, Ghent University and Ghent University Hospital, Ghent, Belgium
| | - Tania Maes
- Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
| | - Ken R Bracke
- Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
| | - Christophe Casteleyn
- Department of Morphology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.,Applied Veterinary Morphology, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Wilrijk, Belgium
| | | | - Thomas Horvatits
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Valentin Fuhrmann
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hans Van Vlierberghe
- Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent University Hospital, Ghent, Belgium
| | - Christophe Van Steenkiste
- Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent University Hospital, Ghent, Belgium
| | - Lindsey Devisscher
- Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent University Hospital, Ghent, Belgium
| | - Isabelle Colle
- Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent University Hospital, Ghent, Belgium
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25
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Soulaidopoulos S, Cholongitas E, Giannakoulas G, Vlachou M, Goulis I. Review article: Update on current and emergent data on hepatopulmonary syndrome. World J Gastroenterol 2018; 24:1285-1298. [PMID: 29599604 PMCID: PMC5871824 DOI: 10.3748/wjg.v24.i12.1285] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 03/01/2018] [Accepted: 03/06/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatopulmonary syndrome (HPS) is a frequent pulmonary complication of end-stage liver disease, characterized by impaired arterial oxygenation induced by intrapulmonary vascular dilatation. Its prevalence ranges from 4% to 47% in patients with cirrhosis due to the different diagnostic criteria applied among different studies. Nitric oxide overproduction and angiogenesis seem to be the hallmarks of a complicated pathogenetic mechanism, leading to intrapulmonary shunting and ventilation-perfusion mismatch. A classification of HPS according to the severity of hypoxemia has been suggested. Contrast-enhanced echocardiography represents the gold standard method for the detection of intrapulmonary vascular dilatations which is required, in combination with an elevated alveolar arterial gradient to set the diagnosis. The only effective treatment which can modify the syndrome’s natural history is liver transplantation. Although it is usually asymptomatic, HPS imparts a high risk of pretransplantation mortality, independently of the severity of liver disease, while there is variable data concerning survival rates after liver transplantation. The potential of myocardial involvement in the setting of HPS has also gained increasing interest in recent research. The aim of this review is to critically approach the existing literature of HPS and emphasize unclear points that remain to be unraveled by future research.
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Affiliation(s)
- Stergios Soulaidopoulos
- Fourth Department of Internal Medicine, Hippokration General Hospital, Medical School of Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Athens 11527, Greece
| | - George Giannakoulas
- Department of Cardiology, AHEPA University Hospital, Medical School of Aristotle University of Thessaloniki, Thessaloniki 54621, Greece
| | - Maria Vlachou
- Department of Cardiology, AHEPA University Hospital, Medical School of Aristotle University of Thessaloniki, Thessaloniki 54621, Greece
| | - Ioannis Goulis
- Fourth Department of Internal Medicine, Hippokration General Hospital, Medical School of Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
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26
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Abstract
Cirrhosis, the twelfth leading cause of death, accounts for 1.1% of all deaths in the United States. Although there are multiple pulmonary complications associated with liver disease, the most important complications that cause significant morbidity and mortality are hepatopulmonary syndrome, hepatic hydrothorax, and portopulmonary hypertension. Patients with cirrhosis who complain of dyspnea should be evaluated for these complications. This article reviews these complications.
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Affiliation(s)
- Vijaya S Ramalingam
- Division of Pulmonary & Critical Care Medicine, Department of Medicine, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA.
| | - Sikandar Ansari
- Division of Pulmonary & Critical Care Medicine, Department of Medicine, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA
| | - Micah Fisher
- Division of Pulmonary & Critical Care Medicine, Department of Medicine, Emory Clinic 'A', 1365 Clifton Road, Northeast 4th Floor, Atlanta, GA 30322, USA
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Li TH, Lee PC, Lee KC, Hsieh YC, Tsai CY, Yang YY, Huang SF, Tsai TH, Hsieh SL, Hou MC, Lin HC, Lee SD. Down-regulation of common NFκB-iNOS pathway by chronic Thalidomide treatment improves Hepatopulmonary Syndrome and Muscle Wasting in rats with Biliary Cirrhosis. Sci Rep 2016; 6:39405. [PMID: 28009008 PMCID: PMC5180197 DOI: 10.1038/srep39405] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 11/23/2016] [Indexed: 12/22/2022] Open
Abstract
Thalidomide can modulate the TNFα-NFκB and iNOS pathway, which involve in the pathogenesis of hepatopulmonary syndrome (HPS) and muscle wasting in cirrhosis. In bile duct ligated-cirrhotic rats, the increased circulating CD16+ (inflammatory) monocytes and its intracellular TNFα, NFκB, monocyte chemotactic protein (MCP-1) and iNOS levels were associated with increased circulating MCP-1/soluable intercellular cell adehesion molecule-1 (sICAM-1), pulmonary TNFα/NOx, up-regulated M1 polarization, exacerbated angiogenesis and hypoxemia (increased AaPO2) in bronchoalveolar lavage (BAL) fluid and pulmonary homogenates. Meanwhile, a significant correlation was noted between circulating CD16+ monocyte/M1 (%) macrophages in BAL; M1 (%) macrophages in BAL/pulmonary iNOS mRNA expression; pulmonary iNOS mRNA expression/relative pulmonary MVD; pulmonary NOx level/AaPO2; circulating CD16+ monocyte/M1 (%) macrophages in muscle homogenates; 3-nitrotyrosine (representative of peroxynitrite) concentration/M1 (%) macrophages in muscle homogenates. The in vitro data demonstrated an iNOS-dependent inhibition of thalidomide on the TNFα-stimulated angiogenesis and myogenesis in human pulmonary artery endothelial cells (HPAECs) and C2C12 myoblasts. Significantly, the co-culture of CD16+ monocyte from different rats with HPAECs, or co-culture of supernatant of above mixed cultures with HPAECs or C2C12 myoblasts stimulated angiogenesis, migration and myogenesis. Our findings demonstrate that TNFα inhibitor thalidomide markedly diminishes the severity of experimental HPS and muscle wasting by down-regulation of common peripheral and local NFκB-iNOS pathway.
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Affiliation(s)
- Tzu-Hao Li
- Division of Allergy and Immunology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.,Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.,Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Chiayi Branch, Taichung Veterans General Hospital, No. 600, Sec. 2, Shixian Rd., West District, Chiayi City, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, No. 155, Sec. 2, Linong St., Taipei, Taiwan
| | - Pei-Chang Lee
- Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.,Division of Gastroenterology &Hepatology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.,Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan
| | - Kuei-Chuan Lee
- Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.,Division of Gastroenterology &Hepatology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.,Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan
| | - Yun-Cheng Hsieh
- Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.,Division of Gastroenterology &Hepatology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.,Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan
| | - Chang-Youh Tsai
- Division of Allergy and Immunology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.,Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.,Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan
| | - Ying-Ying Yang
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, No. 155, Sec. 2, Linong St., Taipei, Taiwan.,Division of Gastroenterology &Hepatology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.,Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan.,Division of General Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan
| | - Shiang-Fen Huang
- Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.,Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan.,Division of Infection Diseases, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan
| | - Tung-Hu Tsai
- Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan.,Institute of Traditional Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan
| | - Shie-Liang Hsieh
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, No. 155, Sec. 2, Linong St., Taipei, Taiwan.,Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan.,Genomics Research Center, Academia Sinica, 128 Sec. 2, Academia Rd., Nankang, Taipei City, Taiwan
| | - Ming-Chih Hou
- Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.,Division of Gastroenterology &Hepatology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.,Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan
| | - Han-Chieh Lin
- Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.,Division of Gastroenterology &Hepatology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.,Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan
| | - Shou-Dong Lee
- Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan.,Department of Medicine, National Yang-Ming University, No. 155, Sec.2, Linong St., Taipei, Taiwan.,Cheng Hsin General Hospital, No. 45, Cheng Hsin St., Beitou District, Taipei
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28
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Wu W, Zhang J, Yang W, Hu B, Fallon MB. Role of splenic reservoir monocytes in pulmonary vascular monocyte accumulation in experimental hepatopulmonary syndrome. J Gastroenterol Hepatol 2016; 31:1888-1894. [PMID: 27029414 PMCID: PMC5132097 DOI: 10.1111/jgh.13388] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 03/15/2016] [Accepted: 03/17/2016] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND AIM Pulmonary monocyte infiltration plays a significant role in the development of angiogenesis in experimental hepatopulmonary syndrome (HPS) after common bile duct ligation (CBDL). Hepatic monocytes are also increased after CBDL, but the origins remain unclear. Splenic reservoir monocytes have been identified as a major source of monocytes that accumulate in injured tissues. Whether splenic monocytes contribute to monocyte alterations after CBDL is unknown. This study evaluates monocyte distributions and assesses effects of splenectomy on monocyte levels and pulmonary vascular and hepatic abnormalities in experimental HPS. METHODS Splenectomy was performed in CBDL animals. Monocyte levels in different tissues and circulation were assessed with CD68. Pulmonary alterations of HPS were evaluated with vascular endothelial growth factor-A (VEGF-A) levels, angiogenesis, and alveolar-arterial oxygen gradient (AaPO2 ). Liver abnormalities were evaluated with fibrosis (Sirius red), bile duct proliferation (CK-19), and enzymatic changes. RESULTS Monocyte levels increased in the lung and liver after CBDL and were accompanied by elevated circulating monocyte numbers. Splenectomy significantly decreased monocyte accumulation, VEGF-A levels, and angiogenesis in CBDL animal lung and improved AaPO2 levels. In contrast, hepatic monocyte levels, fibrosis, and functional abnormalities were further exacerbated by spleen removal. CONCLUSIONS Splenic reservoir monocytes are a major source for lung monocyte accumulation after CBDL, and spleen removal attenuates the development of experimental HPS. Liver monocytes may have different origins, and accumulation is exacerbated after depletion of splenic reservoir monocytes. Tissue specific monocyte alterations, influenced by the spleen reservoir, have a significant impact on pulmonary complications of liver disease.
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Affiliation(s)
- Wei Wu
- Department of Geriatric Surgery, Xiangya HospitalCentral South UniversityChangshaHunanChina,Division of Gastroenterology, Hepatology and Nutrition, Department of Internal MedicineThe University of Texas Health Science Center at HoustonHoustonTexasUSA
| | - Junlan Zhang
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal MedicineThe University of Texas Health Science Center at HoustonHoustonTexasUSA
| | - Wenli Yang
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal MedicineThe University of Texas Health Science Center at HoustonHoustonTexasUSA
| | - Bingqian Hu
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal MedicineThe University of Texas Health Science Center at HoustonHoustonTexasUSA
| | - Michael B Fallon
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal MedicineThe University of Texas Health Science Center at HoustonHoustonTexasUSA
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29
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Grilo-Bensusan I, Pascasio-Acevedo JM. Hepatopulmonary syndrome: What we know and what we would like to know. World J Gastroenterol 2016; 22:5728-5741. [PMID: 27433086 PMCID: PMC4932208 DOI: 10.3748/wjg.v22.i25.5728] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Revised: 05/26/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatopulmonary syndrome (HPS) is characterized by abnormalities in blood oxygenation caused by the presence of intrapulmonary vascular dilations (IPVD) in the context of liver disease, generally at a cirrhotic stage. Knowledge about the subject is still only partial. The majority of the information about the etiopathogenesis of HPS has been obtained through experiments on animals. Reported prevalence in patients who are candidates for a liver transplantation (LT) varies between 4% and 32%, with a predominance of mild or moderate cases. Although it is generally asymptomatic it does have an impact on their quality of life and survival. The diagnosis requires taking an arterial blood gas sample of a seated patient with alveolar-arterial oxygen gradient (AaO2) ≥ 15 mm Hg, or ≥ 20 mm Hg in those over 64 years of age. The IPVD are identified through a transthoracic contrast echocardiography or a macroaggregated albumin lung perfusion scan (99mTc-MAA). There is currently no effective medical treatment. LT has been shown to reverse the syndrome and improve survival rates, even in severe cases. Therefore the policy of prioritizing LT would appear to increase survival rates. This paper takes a critical and clinical look at the current understanding of HPS, as well as the controversies surrounding it and possible future research.
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30
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Cosarderelioglu C, Cosar AM, Gurakar M, Dagher NN, Gurakar A. Hepatopulmonary Syndrome and Liver Transplantation: A Recent Review of the Literature. J Clin Transl Hepatol 2016; 4:47-53. [PMID: 27047772 PMCID: PMC4807143 DOI: 10.14218/jcth.2015.00044] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 02/10/2016] [Accepted: 02/11/2016] [Indexed: 12/14/2022] Open
Abstract
A severe and common pulmonary vascular complication of liver disease is hepatopulmonary syndrome (HPS). It is a triad of liver dysfunction and/or portal hypertension, intrapulmonary vascular dilatations, and increased alveolar-arterial oxygen gradient. Prevalence varies according to various study groups from 4%-47%. While the most common presenting symptom of HPS is dyspnea, it is usually asymptomatic, and thus all liver transplant candidates should be screened for its presence. Pulse oximetry is a useful screening method, but arterial blood gas examination is the gold standard. If there is an abnormal P (A-a)O2 gradient, microbubble transthoracic echocardiography should be done for diagnosis. Outcome is unpredictable, and there is currently no effective medical therapy. The only effective therapy is considered to be liver transplantation. Complete resolution of HPS after liver transplantation is seen within a year in most HPS patients.
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Affiliation(s)
- Caglar Cosarderelioglu
- Johns Hopkins University School of Medicine, Department of Gastroenterology/Hepatology, Baltimore, MD, USA
| | - Arif M. Cosar
- Johns Hopkins University School of Medicine, Department of Gastroenterology/Hepatology, Baltimore, MD, USA
| | - Merve Gurakar
- Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Nabil N. Dagher
- Johns Hopkins University School of Medicine, Department of Surgery/Liver Transplant, Baltimore, MD, USA
| | - Ahmet Gurakar
- Johns Hopkins University School of Medicine, Department of Gastroenterology/Hepatology, Baltimore, MD, USA
- Correspondence to: Ahmet Gurakar, 720 Rutland Avenue, Ross Research Building, Suite #918, Baltimore, Maryland, 21205, USA, Tel: 410-614-3369, Fax: 410-367-2328, E-mail:
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31
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Fussner LA, Iyer VN, Cartin-Ceba R, Lin G, Watt KD, Krowka MJ. Intrapulmonary vascular dilatations are common in portopulmonary hypertension and may be associated with decreased survival. Liver Transpl 2015; 21:1355-64. [PMID: 26077312 DOI: 10.1002/lt.24198] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Revised: 06/01/2015] [Accepted: 06/11/2015] [Indexed: 12/17/2022]
Abstract
Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH) are pulmonary vascular complications of portal hypertension with divergent clinicopathologic features and management. The presence of intrapulmonary vascular dilatations (IPVDs), detected by agitated saline contrast-enhanced transthoracic echocardiography (cTTE), is an essential feature of HPS but is not typically characteristic of POPH. Although IPVDs have been reported rarely in POPH, the prevalence and significance of this finding have not been systematically studied. We conducted a retrospective chart review of 80 consecutive patients diagnosed with POPH from January 1, 2002 to June 30, 2014 with documentation of cTTE findings, pulmonary hemodynamics, oxygenation, and survival. A total of 34 of the 80 patients (42%) underwent cTTE during initial diagnosis of POPH. IPVDs were detected in 20/34 patients (59%); intracardiac shunting was detected in 9/34 patients (26%; 4 also had IPVDs); and 9 patients (26%) had negative cTTE with no evidence of IPVD or intracardiac shunting. Patients with IPVD had decreased survival as compared to those without IPVD (P = 0.003), a trend that persisted after exclusion of liver transplant recipients (P = 0.07). The IPVD group had a trend toward higher Model for End-Stage Liver Disease score with and without incorporating sodium (MELD or MELD-Na; P = 0.05 for both). The right ventricular index of myocardial performance (RIMP) was lower in the IPVD group (median, 0.4 versus 0.6; P = 0.006). Patients with moderate or large IPVDs (n = 6) had worse oxygenation parameters (partial pressure of arterial oxygen, diffusing capacity of the lung for carbon monoxide, and alveolar-arterial oxygen gradient) as compared to the rest of the cohort. Unexpectedly, IPVDs were frequently documented in POPH and associated with decreased survival. To further understand this observation, we recommend screening for IVPD in all patients with POPH.
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Affiliation(s)
| | - Vivek N Iyer
- Divisions of Pulmonary and Critical Care Medicine
| | | | - Grace Lin
- Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
| | - Kymberly D Watt
- Divisions of Gastroenterology and Hepatology, Mayo Clinic Transplant Center, Rochester, Minnesota
| | - Michael J Krowka
- Divisions of Pulmonary and Critical Care Medicine.,Divisions of Gastroenterology and Hepatology, Mayo Clinic Transplant Center, Rochester, Minnesota
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32
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Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis. J Hepatol 2015; 63:1272-84. [PMID: 26192220 DOI: 10.1016/j.jhep.2015.07.004] [Citation(s) in RCA: 422] [Impact Index Per Article: 42.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Revised: 07/06/2015] [Accepted: 07/07/2015] [Indexed: 02/06/2023]
Abstract
The peripheral arterial vasodilation hypothesis has been most influential in the field of cirrhosis and its complications. It has given rise to hundreds of pathophysiological studies in experimental and human cirrhosis and is the theoretical basis of life-saving treatments. It is undisputed that splanchnic arterial vasodilation contributes to portal hypertension and is the basis for manifestations such as ascites and hepatorenal syndrome, but the body of research generated by the hypothesis has revealed gaps in the original pathophysiological interpretation of these complications. The expansion of our knowledge on the mechanisms regulating vascular tone, inflammation and the host-microbiota interaction require a broader approach to advanced cirrhosis encompassing the whole spectrum of its manifestations. Indeed, multiorgan dysfunction and failure likely result from a complex interplay where the systemic spread of bacterial products represents the primary event. The consequent activation of the host innate immune response triggers endothelial molecular mechanisms responsible for arterial vasodilation, and also jeopardizes organ integrity with a storm of pro-inflammatory cytokines and reactive oxygen and nitrogen species. Thus, the picture of advanced cirrhosis could be seen as the result of an inflammatory syndrome in contradiction with a simple hemodynamic disturbance.
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Affiliation(s)
- Mauro Bernardi
- Department of Medical and Surgical Sciences - Alma Mater Studiorum, University of Bologna, Italy; Semeiotica Medica, Policlinico S. Orsola-Malpighi, Bologna, Italy.
| | - Richard Moreau
- Inserm, U(1149), Centre de Recherche sur l'Inflammation (CRI), Paris, France; UMR_S(1149), Université Paris Diderot, Faculté de Médecine, Paris, France; Département Hospitalo-Universitaire (DHU) UNITY, Service d'Hépatologie, Hôpital Beaujon, AP-HP, Clichy, France
| | - Paolo Angeli
- Unit of Hepatic Emergencies and Liver Transplantation, Department of Medicine-DIMED, University of Padova, Padova, Italy
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, United States; Department of Medicine, VA San Diego Healthcare System, San Diego, CA, United States
| | - Vicente Arroyo
- Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomediques Agust Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
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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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34
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Cuadrado A, Díaz A, Iruzubieta P, Salcines JR, Crespo J. Síndrome hepatopulmonar. GASTROENTEROLOGIA Y HEPATOLOGIA 2015; 38:398-408. [DOI: 10.1016/j.gastrohep.2015.02.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2014] [Revised: 02/01/2015] [Accepted: 02/08/2015] [Indexed: 12/17/2022]
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35
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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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36
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Oswald-Mammosser M, Rashid S, Boehm N, Agin A, Geny B, Schini-Kerth V, Charloux A. Effect of the oestrogen receptor antagonist fulvestrant on the cirrhotic rat lung. Fundam Clin Pharmacol 2015; 29:269-77. [PMID: 25753092 DOI: 10.1111/fcp.12114] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Revised: 01/07/2015] [Accepted: 03/04/2015] [Indexed: 01/19/2023]
Abstract
It has been postulated that cirrhosis-related lung vasodilatation and the subsequent hepatopulmonary syndrome are partly explained by an increased estradiol level through an enhanced endothelial formation of nitric oxide (NO). In this study, we assessed whether the oestrogen receptor antagonist fulvestrant (F) improves cirrhosis-related lung abnormalities. Cirrhosis was induced in rats by chronic bile duct ligation (CBDL). Four groups were studied: CBDL, CBDL+F, sham, and sham+F. Histological, immunohistochemical, and Western blot analyses were performed on lung samples. In the lung, the endothelial NO synthase and the nitrotyrosine protein expressions were increased in CBDL as compared to sham rats. Both parameters were significantly reduced by fulvestrant in the CBDL rats. Surprisingly, the level of pVASP (an indirect marker of NO formation and action) was decreased in CBDL rats, and fulvestrant had no effect on this parameter. The level of the vascular endothelial growth factor, the diameter of small lung vessels, and the number of macrophages were increased in CBDL lungs in comparison with sham lungs, and these parameters were unaffected by fulvestrant treatment. In conclusion, fulvestrant may not be relevant to improve lung abnormalities in cirrhosis because NO may not be biologically active and because key events contributing to the lung abnormalities are not affected by fulvestrant.
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Affiliation(s)
- Monique Oswald-Mammosser
- Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique, Hôpitaux Universitaires de Strasbourg et EA 3072, Faculté de Médecine, Université de Strasbourg, Strasbourg, France
| | - Sherzad Rashid
- UMR CNRS 7213, Laboratoire de Biophotonique et de Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France
| | - Nelly Boehm
- Institut d'Histologie et INSERM U1119, Faculté de Médecine, Université de Strasbourg, Strasbourg, France
| | - Arnaud Agin
- Laboratoire d'Hormonologie et Icube, Faculté de Médecine, CNRS, FMTS, Université de Strasbourg, Strasbourg, France
| | - Bernard Geny
- Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique, Hôpitaux Universitaires de Strasbourg et EA 3072, Faculté de Médecine, Université de Strasbourg, Strasbourg, France
| | - Valérie Schini-Kerth
- UMR CNRS 7213, Laboratoire de Biophotonique et de Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France
| | - Anne Charloux
- Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique, Hôpitaux Universitaires de Strasbourg et EA 3072, Faculté de Médecine, Université de Strasbourg, Strasbourg, France
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37
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Chung S, Lee K, Chang SA, Kim DK. Aggravation of hepatopulmonary syndrome after sildenafil treatment in a patient with coexisting portopulmonary hypertension. Korean Circ J 2015; 45:77-80. [PMID: 25653708 PMCID: PMC4310984 DOI: 10.4070/kcj.2015.45.1.77] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 05/16/2014] [Accepted: 06/12/2014] [Indexed: 01/27/2023] Open
Abstract
Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPHTN) are complications of portal hypertension and cirrhosis. Their pathophysiological mechanisms clearly differ. HPS is characterized by a defect in arterial oxygenation induced by pulmonary vascular dilatation. In contrast, PPHTN is predominantly due to excessive pulmonary vasoconstriction and vascular remodeling, but is rarely associated with hypoxia. We report a case of a patient who had both HPS and PPHTN at the time of presentation. HPS was aggravated after sildenafil administration for the treatment of PPHTN. We demonstrated increased amount of intrapulmonay shunt after sildenafil challenge by using agitated saline contrast transthoracic echocardiography.
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Affiliation(s)
- Seungmin Chung
- Division of Cardiology, Heart, Vascular and Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyungho Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung-A Chang
- Division of Cardiology, Heart, Vascular and Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Duk-Kyung Kim
- Division of Cardiology, Heart, Vascular and Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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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 induces severe hypoxaemia. Considering the favourable long-term survival of HPS patients as well as the reversal of the syndrome with a functional liver graft, HPS is now an indication for orthotopic liver transplantation (OLT). Consequently, blood gas analysis and imaging techniques should be performed when cirrhotic patients present with shortness of breath as well as when OLT candidates are placed on the transplant waiting list. If the arterial partial pressure of oxygen (PaO2) is more than 10.7 kPa when breathing room air, HPS can be excluded and no other investigation is needed. When the PaO2 when breathing room air is 10.7 kPa or less, contrast-enhanced echocardiography should be performed to exclude pulmonary vascular dilatation. Lung function tests may also help detect additional pulmonary diseases that can contribute to impaired oxygenation. When contrast-enhanced echocardiography is negative, HPS is excluded and no follow-up is needed. When contrast-enhanced echocardiography is positive and PaO2 less than 8 kPa, patients should obtain a severity score that provides them with a reasonable probability of being transplanted within 3 months. In mild-to-moderate HPS (PaO2 8 to 10.6 kPa), periodic follow-up is recommended every 3 months to detect any further deterioration in PaO2. Although no intraoperative deaths have been directly attributed to HPS, oxygenation may worsen immediately following OLT due to volume overload and postoperative infections. Mechanical ventilation is often prolonged with an extended stay in the ICU. A high postoperative mortality (mostly within 6 months) is observed in this group of patients in comparison to non-HPS patients. However, the recovery of an adequate PaO2 within 12 months after OLT explains the similar outcome of HPS and non-HPS patients following OLT over a longer time period.
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Probiotics (VSL#3) prevent endothelial dysfunction in rats with portal hypertension: role of the angiotensin system. PLoS One 2014; 9:e97458. [PMID: 24832090 PMCID: PMC4022585 DOI: 10.1371/journal.pone.0097458] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Accepted: 04/21/2014] [Indexed: 02/07/2023] Open
Abstract
AIMS Portal hypertension characterized by generalized vasodilatation with endothelial dysfunction affecting nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) has been suggested to involve bacterial translocation and/or the angiotensin system. The possibility that ingestion of probiotics prevents endothelial dysfunction in rats following common bile duct ligation (CBDL) was evaluated. METHODS Rats received either control drinking water or the probiotic VSL#3 solution (50 billion bacteria.kg body wt⁻¹.day⁻¹) for 7 weeks. After 3 weeks, rats underwent surgery with either resection of the common bile duct or sham surgery. The reactivity of mesenteric artery rings was assessed in organ chambers, expression of proteins by immunofluorescence and Western blot analysis, oxidative stress using dihydroethidium, and plasma pro-inflammatory cytokine levels by flow cytometry. RESULTS Both NO- and EDH-mediated relaxations to acetylcholine were reduced in the CBDL group compared to the sham group, and associated with a reduced expression of Cx37, Cx40, Cx43, IKCa and SKCa and an increased expression of endothelial NO synthase (eNOS). In aortic sections, increased expression of NADPH oxidase subunits, angiotensin converting enzyme, AT1 receptors and angiotensin II, and formation of ROS and peroxynitrite were observed. VSL#3 prevented the deleterious effect of CBDL on EDH-mediated relaxations, vascular expression of connexins, IKCa, SKCa and eNOS, oxidative stress, and the angiotensin system. VSL#3 prevented the CBDL-induced increased plasma TNF-α, IL-1α and MCP-1 levels. CONCLUSIONS These findings indicate that VSL#3 ingestion prevents endothelial dysfunction in the mesenteric artery of CBDL rats, and this effect is associated with an improved vascular oxidative stress most likely by reducing bacterial translocation and the local angiotensin system.
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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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Abstract
PURPOSE OF REVIEW To discuss the advances in the understanding of the pathophysiology of experimental and human hepatopulmonary syndrome (HPS) and in the management of HPS, particularly regarding liver transplantation. RECENT FINDINGS Advances have been made in defining the pathophysiology of HPS in experimental models as well as in human disease, including the role of endothelin-1, pulmonary monocytes, and angiogenesis. Additionally, the implications of the presence of HPS as it relates to prioritizing patients for liver transplantation and posttransplant outcomes will also be reviewed. SUMMARY Mechanisms of disease continue to be defined in HPS, providing potential targets for pharmacologic intervention. Outcomes after liver transplantation are also becoming clearer, including the management of HPS with severe hypoxemia.
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Shikata F, Sakaue T, Nakashiro KI, Okazaki M, Kurata M, Okamura T, Okura M, Ryugo M, Nakamura Y, Yasugi T, Higashiyama S, Izutani H. Pathophysiology of lung injury induced by common bile duct ligation in mice. PLoS One 2014; 9:e94550. [PMID: 24733017 PMCID: PMC3986091 DOI: 10.1371/journal.pone.0094550] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Accepted: 03/17/2014] [Indexed: 12/13/2022] Open
Abstract
Background Liver dysfunction and cirrhosis affect vasculature in several organ systems and cause impairment of organ functions, thereby increasing morbidity and mortality. Establishment of a mouse model of hepatopulmonary syndrome (HPS) would provide greater insights into the genetic basis of the disease. Our objectives were to establish a mouse model of lung injury after common bile duct ligation (CBDL) and to investigate pulmonary pathogenesis for application in future therapeutic approaches. Methods Eight-week-old Balb/c mice were subjected to CBDL. Immunohistochemical analyses and real-time quantitative reverse transcriptional polymerase chain reaction were performed on pulmonary tissues. The presence of HPS markers was detected by western blot and microarray analyses. Results We observed extensive proliferation of CD31-positive pulmonary vascular endothelial cells at 2 weeks after CBDL and identified 10 upregulated and 9 down-regulated proteins that were associated with angiogenesis. TNF-α and MMP-9 were highly expressed at 3 weeks after CBDL and were less expressed in the lungs of the control group. Conclusions We constructed a mouse lung injury model by using CBDL. Contrary to our expectation, lung pathology in our mouse model exhibited differences from that of rat models, and the mechanisms responsible for these differences are unknown. This phenomenon may be explained by contrasting processes related to TNF induction of angiogenic signaling pathways in the inflammatory phase. Thus, we suggest that our mouse model can be applied to pulmonary pathological analyses in the inflammatory phase, i.e., to systemic inflammatory response syndrome, acute lung injury, and multiple organ dysfunction syndrome.
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Affiliation(s)
- Fumiaki Shikata
- Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Tomohisa Sakaue
- Department of Cell Growth and Tumor Regulation, Ehime University, Proteo-Science Center, Ehime University, Ehime, Japan
- Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Koh-ichi Nakashiro
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Mikio Okazaki
- Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Mie Kurata
- Department of Pathology, Division of Pathogenomics, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Toru Okamura
- Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Masahiro Okura
- Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Masahiro Ryugo
- Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Yuki Nakamura
- Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Takumi Yasugi
- Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Shigeki Higashiyama
- Department of Cell Growth and Tumor Regulation, Ehime University, Proteo-Science Center, Ehime University, Ehime, Japan
- Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Hironori Izutani
- Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Ehime, Japan
- * E-mail:
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Zhang J, Yang W, Hu B, Wu W, Fallon MB. Endothelin-1 activation of the endothelin B receptor modulates pulmonary endothelial CX3CL1 and contributes to pulmonary angiogenesis in experimental hepatopulmonary syndrome. THE AMERICAN JOURNAL OF PATHOLOGY 2014; 184:1706-14. [PMID: 24731444 DOI: 10.1016/j.ajpath.2014.02.027] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Revised: 01/29/2014] [Accepted: 02/11/2014] [Indexed: 02/06/2023]
Abstract
Hepatic production and release of endothelin-1 (ET-1) binding to endothelin B (ETB) receptors, overexpressed in the lung microvasculature, is associated with accumulation of pro-angiogenic monocytes and vascular remodeling in experimental hepatopulmonary syndrome (HPS) after common bile duct ligation (CBDL). We have recently found that lung vascular monocyte adhesion and angiogenesis in HPS involve interaction of endothelial C-X3-C motif ligand 1 (CX3CL1) with monocyte CX3C chemokine receptor 1 (CX3CR1), although whether ET-1/ETB receptor activation influences these events is unknown. Our aim was to define if ET-1/ETB receptor activation modulates CX3CL1/CX3CR1 signaling and lung angiogenesis in experimental HPS. A selective ETB receptor antagonist, BQ788, was given for 2 weeks to 1-week CBDL rats. ET-1 (±BQ788) was given to cultured rat pulmonary microvascular endothelial cells overexpressing ETB receptors. BQ788 treatment significantly decreased lung angiogenesis, monocyte accumulation, and CX3CL1 levels after CBDL. ET-1 treatment significantly induced CX3CL1 production in lung microvascular endothelial cells, which was blocked by inhibitors of Ca(2+) and mitogen-activated protein kinase (MEK)/ERK pathways. ET-1-induced ERK activation was Ca(2+) independent. ET-1 administration also increased endothelial tube formation in vitro, which was inhibited by BQ788 or by blocking Ca(2+) and MEK/ERK activation. CX3CR1 neutralizing antibody partially inhibited ET-1 effects on tube formation. These findings identify a novel mechanistic interaction between the ET-1/ETB receptor axis and CX3CL1/CX3CR1 in mediating pulmonary angiogenesis and vascular monocyte accumulation in experimental HPS.
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Affiliation(s)
- Junlan Zhang
- Division of Gastroenterology, Hepatology, and Nutrition, the Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Wenli Yang
- Division of Gastroenterology, Hepatology, and Nutrition, the Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Bingqian Hu
- Division of Gastroenterology, Hepatology, and Nutrition, the Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Wei Wu
- Division of Gastroenterology, Hepatology, and Nutrition, the Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Michael B Fallon
- Division of Gastroenterology, Hepatology, and Nutrition, the Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas.
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Machicao VI, Balakrishnan M, Fallon MB. Pulmonary complications in chronic liver disease. Hepatology 2014; 59:1627-37. [PMID: 24089295 DOI: 10.1002/hep.26745] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Accepted: 09/12/2013] [Indexed: 12/13/2022]
Abstract
The association of chronic liver disease with respiratory symptoms and hypoxia is well recognized. Over the last century, three pulmonary complications specific to chronic liver disease have been characterized: hepatopulmonary syndrome (HPS), portopulmonary hypertension (POPH), and hepatic hydrothorax (HH). The development of portal hypertension is fundamental in the pathogenesis of each of these disorders. HPS is the most common condition, found in 5%-30% of cirrhosis patients, manifested by abnormal oxygenation due to the development of intrapulmonary vascular dilatations. The presence of HPS increases mortality and impairs quality of life, but is reversible with liver transplantation (LT). POPH is characterized by development of pulmonary arterial hypertension in the setting of portal hypertension, and is present in 5%-10% of cirrhosis patients evaluated for LT. Screening for POPH in cirrhosis patients eligible for LT is critical since severe POPH is a relative contraindication for LT. Patients with moderate POPH, who respond adequately to medical therapy, may benefit from LT, although sufficient controlled data are lacking. HH is a transudative pleural effusion seen in 5%-10% of cirrhosis patients, in the absence of cardiopulmonary disease. Diagnosis of HH should prompt consideration for LT, which is the ultimate treatment for HH. Conservative management includes salt restriction and diuretics, with thoracentesis and transjugular intrahepatic portosystemic shunt (TIPS) as second-line therapeutic options.
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Affiliation(s)
- Victor I Machicao
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX
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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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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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Transition from hepatopulmonary syndrome to portopulmonary hypertension: a case series of 3 patients. Case Rep Pulmonol 2013; 2013:561870. [PMID: 24324910 PMCID: PMC3844212 DOI: 10.1155/2013/561870] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Accepted: 10/02/2013] [Indexed: 01/27/2023] Open
Abstract
Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPHTN) are the two major pulmonary vascular complications of liver disease. While HPS is characterized by low pulmonary vascular resistance, PPHTN is defined by the presence of elevated pulmonary vascular resistance. Given these seemingly opposing pathophysiologic mechanisms, these conditions were traditionally felt to be mutually exclusive. In this series, we present three patients with severe hepatopulmonary syndrome who had spontaneous resolution of their HPS with the subsequent development of PPHTN. To our knowledge, this is the largest case series presented of this phenomenon in nontransplanted patients. One proposed mechanism for the occurrence of this phenomenon involves dysregulation of the same vascular signaling pathway, which may lead to both pulmonary vascular dilatations and pulmonary arterial remodeling in the same patient. Another theory involves the possible differential binding of endothelin-1, a vasoactive signaling peptide that induces vasoconstriction when bound to receptor A and vasodilation when bound to receptor B. Although the mechanisms for this phenomenon remain unclear, it is important to be vigilant of this phenomenon as it may change the patient's overall treatment plan, especially in regard to appropriateness and timing of liver transplant.
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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] [MESH Headings] [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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Tanikella R, Fallon MB. Hepatopulmonary syndrome and liver transplantation: who, when, and where? Hepatology 2013; 57:2097-9. [PMID: 23471874 PMCID: PMC10963044 DOI: 10.1002/hep.26367] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Revised: 02/19/2013] [Accepted: 02/23/2013] [Indexed: 12/15/2022]
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Du QH, Han L, Jiang JJ, Li PT, Wang XY, Jia X. Increased endothelin receptor B and G protein coupled kinase-2 in the mesentery of portal hypertensive rats. World J Gastroenterol 2013; 19:2065-2072. [PMID: 23599626 PMCID: PMC3623984 DOI: 10.3748/wjg.v19.i13.2065] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2012] [Accepted: 02/06/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To elucidate the mechanisms of mesenteric vasodilation in portal hypertension (PHT), with a focus on endothelin signaling.
METHODS: PHT was induced in rats by common bile duct ligation (CBDL). Portal pressure (PP) was measured directly via catheters placed in the portal vein tract. The level of endothelin-1 (ET-1) in the mesenteric circulation was determined by radioimmunoassay, and the expression of the endothelin A receptor (ETAR) and endothelin B receptor (ETBR) was assessed by immunofluorescence and Western blot. Additionally, expression of G protein coupled kinase-2 (GRK2) and β-arrestin 2, which influence endothelin receptor sensitivity, were also studied by Western blot.
RESULTS: PP of CBDL rats increased significantly (11.89 ± 1.38 mmHg vs 16.34 ± 1.63 mmHg). ET-1 expression decreased in the mesenteric circulation 2 and 4 wk after CBDL. ET-1 levels in the systemic circulation of CBDL rats were increased at 2 wk and decreased at 4 wk. There was no change in ETAR expression in response to CBDL; however, increased expression of ETBR in the endothelial cells of mesenteric arterioles and capillaries was observed. In sham-operated rats, ETBR was mainly expressed in the CD31+ endothelial cells of the arterioles. With development of PHT, in addition to the endothelial cells, ETBR expression was noticeably detectable in the SMA+ smooth muscle cells of arterioles and in the CD31+ capillaries. Following CBDL, increased expression of GRK2 was also found in mesenteric tissue, though there was no change in the level of β-arrestin 2.
CONCLUSION: Decreased levels of ET-1 and increased ETBR expression in the mesenteric circulation following CBDL in rats may underlie mesenteric vasodilation in individuals with PHT. Mechanistically, increased GRK2 expression may lead to desensitization of ETAR, as well as other vasoconstrictors, promoting this vasodilatory effect.
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