|
1
|
Chen J, Guo Y, Zhang X, Zhou D, Zhou Y, Pan Q, Chai J, Gao J. Disruption of Hepatic Sinusoidal Homeostasis Leads to Hepatopulmonary Syndrome. J Cell Mol Med 2025; 29:e70585. [PMID: 40344298 PMCID: PMC12061640 DOI: 10.1111/jcmm.70585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 04/22/2025] [Accepted: 04/26/2025] [Indexed: 05/11/2025] Open
Abstract
Hepatopulmonary syndrome (HPS) is a pulmonary vascular complication of liver disease and/or portal hypertension. HPS manifests as impaired gas exchange and hypoxemia due to intrapulmonary vascular dilatations and shunts. In response to primary liver disease, the abnormal adaptation of respiratory epithelial cells, pulmonary endothelial cells and immune cells leads to pulmonary microenvironment disequilibrium and HPS. In this review, we explore the pathophysiologic mechanisms of HPS, including vascular dilation, angiogenesis and alveolar dysfunction. The liver is the primary contributor to HPS, and liver transplantation is the only treatment that generally reverses HPS. We then discuss how disruption of hepatic sinusoidal homeostasis may impact the progression of HPS, mainly focusing on hepatocytes, cholangiocytes, LSECs and macrophages. As HPS occurs more commonly in advanced liver cirrhosis, we also discuss that normalisation of liver dysfunction and portal hypertension is crucial for the resolution of HPS. In conclusion, liver-targeted therapies may be effective in treating HPS.
Collapse
Affiliation(s)
- Jiaxin Chen
- Department of Gastroenterology, Lab of Gastroenterology and HepatologyWest China Hospital, Sichuan UniversityChengduChina
| | - Yangkun Guo
- Department of Gastroenterology, Lab of Gastroenterology and HepatologyWest China Hospital, Sichuan UniversityChengduChina
| | - Xiaoxun Zhang
- Department of Gastroenterology, Institute of Digestive Disease of PLA, Cholestatic Liver Diseases Center and Center for Metabolic Associated Fatty Liver DiseaseThe First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University)ChongqingChina
| | - Dengcheng Zhou
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, College of Life SciencesSichuan UniversityChengduChina
| | - Yongfang Zhou
- Department of Respiratory CareWest China Hospital of Sichuan UniversityChengduSichuanChina
| | - Qiong Pan
- Department of Gastroenterology, Institute of Digestive Disease of PLA, Cholestatic Liver Diseases Center and Center for Metabolic Associated Fatty Liver DiseaseThe First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University)ChongqingChina
| | - Jin Chai
- Department of Gastroenterology, Institute of Digestive Disease of PLA, Cholestatic Liver Diseases Center and Center for Metabolic Associated Fatty Liver DiseaseThe First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University)ChongqingChina
| | - Jinhang Gao
- Department of Gastroenterology, Lab of Gastroenterology and HepatologyWest China Hospital, Sichuan UniversityChengduChina
| |
Collapse
|
|
2
|
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.
Collapse
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
| |
Collapse
|
|
3
|
Alam A, Ozturk NB, Akyuz F. Hepatopulmonary syndrome unveiled: Exploring pathogenesis, diagnostic approaches, and therapeutic strategies. HEPATOLOGY FORUM 2024; 6:29-33. [PMID: 40255956 PMCID: PMC12008457 DOI: 10.14744/hf.2024.2024.0001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 02/29/2024] [Accepted: 03/22/2024] [Indexed: 04/22/2025]
Abstract
Hepatopulmonary syndrome (HPS) is a pulmonary complication of liver cirrhosis that causes an oxygenation defect. Many patients are asymptomatic at diagnosis or may have non-specific symptoms such as dyspnea. Since the diagnostic criteria for HPS have been established, its prevalence has been better estimated. HPS is an important prognostic indicator for patients undergoing evaluation for liver transplant. The implementation of the Model for End-stage Liver Disease exception policy has improved the outcomes of HPS; however, the mortality remains high. Here, we discuss the pathophysiology, diagnostic criteria, and recent experimental studies in HPS.
Collapse
Affiliation(s)
- Anusha Alam
- Department of Internal Medicine, Beaumont Hospital, Michigan, United States
| | - Nazli Begum Ozturk
- Department of Internal Medicine, Beaumont Hospital, Michigan, United States
| | - Filiz Akyuz
- Department of Gastroenterology and Hepatology, Istanbul University School of Medicine, Istanbul, Turkiye
| |
Collapse
|
|
4
|
Chinese Society of Gastroenterology, Chinese Medical Association. Chinese consensus on the management of liver cirrhosis. J Dig Dis 2024; 25:332-352. [PMID: 39044465 DOI: 10.1111/1751-2980.13294] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 05/19/2024] [Accepted: 06/11/2024] [Indexed: 07/25/2024]
Abstract
Liver cirrhosis, characterized by diffuse necrosis, insufficient regeneration of hepatocytes, angiogenesis, severe fibrosis, and the formation of pseudolobules, is a progressive, chronic liver disease induced by a variety of causes. It is clinically characterized by liver function damage and portal hypertension, and many complications may occur in its late stage. Based on the updated practice guidelines, expert consensuses, and research advances on the diagnosis and treatment of cirrhosis, the Chinese Society of Gastroenterology of Chinese Medical Association established the current consensus to standardize the clinical diagnosis and management of liver cirrhosis and guide clinical practice. This consensus contains 43 statements on the etiology, pathology and pathogenesis, clinical manifestations, major complications, diagnosis, treatment, prognosis, and chronic disease control of liver cirrhosis. Since several practice guidelines and expert consensuses on the complications of liver cirrhosis have been published, this consensus emphasizes the research progress of liver cirrhosis itself.
Collapse
|
|
5
|
Sayadi A, Duhaut L, Robert F, Savale L, Coilly A. [Hepatopulmonary syndrome]. Rev Med Interne 2024; 45:156-165. [PMID: 37005097 DOI: 10.1016/j.revmed.2023.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 03/07/2023] [Accepted: 03/17/2023] [Indexed: 04/03/2023]
Abstract
The hepatopulmonary syndrome (HPS) is one of the lung diseases associated with cirrhosis and portal hypertension. It should be discussed for any dyspnea in cirrhotic patients. HPS is a pulmonary vascular disease characterized by intrapulmonary vascular dilatations (IPVD). The pathogenesis is complex and seems to rely on communications between the portal and pulmonary circulations. The diagnosis is based on a triad of liver disease and portal hypertension, evidence of IPVDs, and impaired gas exchange (alveolar-arterial oxygen difference [A-aO2]≥15mmHg). HPS impairs prognosis (23% survival at 5years) and patients' quality of life. Liver transplantation (LT) allows regression of IPDVD in almost 100% of cases, normalization of gas exchange and improves survival with a 5-year post-LT survival between 76 and 87%. It is the only curative treatment, indicated in patients with severe HPS, defined by an arterial partial pressure of oxygen (PaO2) below 60mmHg. When LT is not indicated or feasible, long-term oxygen therapy may be proposed as a palliative treatment. A better understanding of the pathophysiological mechanisms is needed to improve the therapeutic possibilities in a near future.
Collapse
Affiliation(s)
- A Sayadi
- UMR-S 1193, hôpital Paul-Brousse, centre hépato-biliaire, université Paris-Saclay, AP-HP, 94800 Villejuif, France
| | - L Duhaut
- UMR-S 1193, hôpital Paul-Brousse, centre hépato-biliaire, université Paris-Saclay, AP-HP, 94800 Villejuif, France
| | - F Robert
- Inserm UMR_S 999, 94270 Le Kremlin-Bicêtre, France
| | - L Savale
- Inserm UMR_S 999, 94270 Le Kremlin-Bicêtre, France; Service de pneumologie, hôpital Bicêtre, université Paris-Saclay, AP-HP, 94270 Le Kremlin-Bicêtre, France
| | - A Coilly
- UMR-S 1193, hôpital Paul-Brousse, centre hépato-biliaire, université Paris-Saclay, AP-HP, 94800 Villejuif, France.
| |
Collapse
|
|
6
|
Panackel C, Fawaz M, Jacob M, Raja K. Pulmonary Assessment of the Liver Transplant Recipient. J Clin Exp Hepatol 2023; 13:895-911. [PMID: 37693254 PMCID: PMC10483013 DOI: 10.1016/j.jceh.2023.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 04/13/2023] [Indexed: 09/12/2023] Open
Abstract
Respiratory symptoms and hypoxemia can complicate chronic liver disease and portal hypertension. Various pulmonary disorders affecting the pleura, lung parenchyma, and pulmonary vasculature are seen in end-stage liver disease, complicating liver transplantation (LT). Approximately 8% of cirrhotic patients in an intensive care unit develop severe pulmonary problems. These disorders affect waiting list mortality and posttransplant outcomes. A thorough history, physical examination, and appropriate laboratory tests help diagnose and assess the severity to risk stratify pulmonary diseases before LT. Hepatopulmonary syndrome (HPS), portopulmonary hypertension (POPH), and hepatic hydrothorax (HH) are respiratory consequences specific to cirrhosis and portal hypertension. HPS is seen in 5-30% of cirrhosis cases and is characterized by impaired oxygenation due to intrapulmonary vascular dilatations and arteriovenous shunts. Severe HPS is an indication of LT. The majority of patients with HPS resolve their hypoxemia after LT. When pulmonary arterial hypertension occurs in patients with portal hypertension, it is called POPH. All other causes of pulmonary arterial hypertension should be ruled out before labeling as POPH. Since severe POPH (mean pulmonary artery pressure [mPAP] >50 mm Hg) is a relative contraindication for LT, it is crucial to screen for POPH before LT. Those with moderate POPH (mPAP >35 mm Hg), who improve with medical therapy, will benefit from LT. A transudative pleural effusion called hepatic hydrothorax (HH) is seen in 5-10% of people with cirrhosis. Refractory cases of HH benefit from LT. In recent years, increasing clinical expertise and advances in the medical field have resulted in better outcomes in patients with moderate to severe pulmonary disorders, who undergo LT.
Collapse
Affiliation(s)
| | - Mohammed Fawaz
- Integrated Liver Care, Aster Medcity, Kochi, Kerala, India
| | - Mathew Jacob
- Integrated Liver Care, Aster Medcity, Kochi, Kerala, India
| | - Kaiser Raja
- King's College Hospital London, Dubai Hills, Dubai, United Arab Emirates
| |
Collapse
|
|
7
|
Tan YW, Agrawal RV, Pan TLT, Muthiah MD, Teo FSW, Wong WH. Pentoxifylline therapy for persistent hepatopulmonary syndrome after liver transplantation. Singapore Med J 2023:384046. [PMID: 37675673 DOI: 10.4103/singaporemedj.smj-2021-246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/08/2023]
Affiliation(s)
- Yi Wei Tan
- Department of Anesthesia, National University Health System, Singapore
| | | | - Terry Ling Te Pan
- Department of Anesthesia, National University Health System, Singapore
| | - Mark Dhinesh Muthiah
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; Division of Gastroenterology and Hepatology, National University Hospital; National University Centre for Organ Transplantation, National University Health System, Singapore
| | - Felicia Su Wei Teo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; Division of Respiratory and Critical Care Medicine, Department of Medicine, National University Hospital, Singapore
| | - Weng Hoa Wong
- Department of Anesthesia, National University Health System, Singapore
| |
Collapse
|
|
8
|
Gandhi KD, Taweesedt PT, Sharma M, Surani S. Hepatopulmonary syndrome: An update. World J Hepatol 2021; 13:1699-1706. [PMID: 34904039 PMCID: PMC8637683 DOI: 10.4254/wjh.v13.i11.1699] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 06/25/2021] [Accepted: 08/31/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatopulmonary syndrome (HPS) is characterized by defects in oxygenation caused by intra-pulmonary vasodilation occurring because of chronic liver disease, portal hypertension, or congenital portosystemic shunts. Clinical implications of portal hypertension are very well-known, however, awareness of its effect on multiple organs such as the lungs are less known. The presence of HPS in chronic liver disease is associated with increased mortality. Medical therapies available for HPS have not been proven effective and definitive treatment for HPS is mainly liver transplantation (LT). LT improves mortality for patients with HPS drastically. This article provides a review on the definition, clinical presentation, diagnosis, and management of HPS.
Collapse
Affiliation(s)
- Kejal D Gandhi
- Department of Internal Medicine, Medstar Washington Hospital Center/Georgetown University, Washigton, DC 20010, United States
| | - Pahnwat Tonya Taweesedt
- Department of Medicine, Corpus Christi Medical Center, Corpus Christi, TX 78412, United States
| | - Munish Sharma
- Department of Medicine, Corpus Christi Medical Center, Corpus Christi, TX 78412, United States
| | - Salim Surani
- Department of Medicine, Texas A&M University, Bryan, TX 78413, United States
- Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, United States.
| |
Collapse
|
|
9
|
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.
Collapse
|
|
10
|
Aragon Pinto C, Iyer VN, Albitar HAH, Anderson A, Cajigas H, Simonetto DA, Krowka MJ, DuBrock HM, Gallo de Moraes A. Outcomes of liver transplantation in patients with hepatopulmonary syndrome in the pre and post-MELD eras: A systematic review. Respir Med Res 2021; 80:100852. [PMID: 34418867 DOI: 10.1016/j.resmer.2021.100852] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/15/2021] [Accepted: 07/12/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND The lack of large hepatopulmonary syndrome cohorts undergoing liver transplantation (LT) has resulted in limited information about post-LT outcomes and expectations. METHODS The long and short-term outcomes of LT in patients with hepatopulmonary syndrome (HPS) were evaluated before and after the implementation of Model for Endstage Liver Disease (MELD) score in 2002, granting exception points for patients with HPS. PubMed/Medline, Embase, Web of Science and Scopus databases were searched for published and unpublished studies from 01/1990 to 04/2019. Studies that included HPS patients who underwent LT and reported post-LT outcomes and HPS severity were reviewed. After reviewing the full text of 1421 articles, 30 were included in the pre-MELD era (before 2002) and 60 in the post-MELD era. RESULTS A total of 598 patients (210 children and 388 adults) with HPS who underwent LT were included in this systematic review. In children, 5-year survival probability was similar in the pre and post-MELD groups (85.7% vs. 97.4; p = 0.09). Median post-transplant PaO2 in room air was higher in the post-MELD group (71 [53-87] vs. 97 [80-108] mmHg: p = 0.008). In adults, 5-year survival probability was higher in the post-MELD era (73 vs. 87.3%; p = 0.008). Median post-transplant PaO2 in room air was higher in post-MELD group (75 [63-85] vs. 87 [75-95] mmHg; p = 0.001).. CONCLUSIONS After MELD exception implementation, survival rates and post-transplant oxygenation improved in adult patients with HPS who underwent liver transplantation, whereas only post-transplant oxygenation improved in children.
Collapse
Affiliation(s)
- Catarina Aragon Pinto
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA; Mayo Epidemiology and Translational Research in Intensive Care group (METRIC), Mayo Clinic, Rochester, MN, USA
| | - Vivek N Iyer
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
| | | | - Alexandra Anderson
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA
| | - Hector Cajigas
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Douglas A Simonetto
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Michael J Krowka
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
| | - Hilary M DuBrock
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
| | - Alice Gallo de Moraes
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA; Mayo Epidemiology and Translational Research in Intensive Care group (METRIC), Mayo Clinic, Rochester, MN, USA.
| |
Collapse
|
|
11
|
Henkel S, Vetterly C, Squires R, McKiernan P, Squires J. Pharmacological management of portal hypertension and its complications in children: lessons from adults and opportunities for the future. Expert Opin Pharmacother 2020; 22:291-304. [PMID: 33074032 DOI: 10.1080/14656566.2020.1825685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
INTRODUCTION Portal hypertension (PHT) and its complications in children are thought to be distinct from adult PHT in several areas, including the underlying bio-physiology of a child in which PHT develops, but also because of the pediatric-specific etiologies that drive disease progression. And yet pharmacologic approaches to PHT in children are mainly based on adult data, modified for pediatric practice. This reality has been driven by a lack of data specific to children. AREAS COVERED The authors discuss current therapeutic approaches to PHT in children, including management of acute gastrointestinal variceal bleed, pharmacotherapy in prophylaxis, and established and emerging therapies to combat systemic co-morbidities that result from PHT. The few areas where pediatric-specific data exist are highlighted and the many gaps in knowledge that remain unresolved are underscored. EXPERT OPINION Despite decades of experience, optimal management of pediatric PHT remains undefined. In large part, this can be directly linked to a lack of basic understanding related to the unique pathophysiology and natural history that defines PHT in children. As a result, meaningful research into the utility and effectiveness of pharmacotherapy in children with PHT remains in its infancy. Large, multi-center, prospective studies will be needed to begin to establish an infrastructure on which a pediatric-specific research agenda can be built.
Collapse
Affiliation(s)
- Sarah Henkel
- Division of Gastroenterology and Hepatology, UPMC Children's Hospital of Pittsburgh , Pittsburgh, PA
| | - Carol Vetterly
- Department of Pharmacy, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Pharmacy , Pittsburgh, PA
| | - Robert Squires
- Division of Gastroenterology and Hepatology, UPMC Children's Hospital of Pittsburgh , Pittsburgh, PA
| | - Patrick McKiernan
- Division of Gastroenterology and Hepatology, UPMC Children's Hospital of Pittsburgh , Pittsburgh, PA
| | - James Squires
- Division of Gastroenterology and Hepatology, UPMC Children's Hospital of Pittsburgh , Pittsburgh, PA
| |
Collapse
|
|
12
|
Weinfurtner K, Forde K. Hepatopulmonary Syndrome and Portopulmonary Hypertension: Current Status and Implications for Liver Transplantation. CURRENT HEPATOLOGY REPORTS 2020; 19:174-185. [PMID: 32905452 PMCID: PMC7473417 DOI: 10.1007/s11901-020-00532-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
PURPOSE OF REVIEW Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PoPH) are both pulmonary vascular complications of advanced liver disease; however, these syndromes have distinct pathophysiology, clinical implications, and management. RECENT FINDINGS While both conditions are associated with portal hypertension, HPS results from diffuse pulmonary capillary vasodilation and PoPH results from vasoconstriction and vascular remodeling of pulmonary arteries. In HPS, no medical therapies clearly improve outcomes; however, patients have excellent post-LT outcomes with near uniform reversal of hypoxemia. In PoPH, several medical therapies used in idiopathic pulmonary hypertension have been shown improve pulmonary hemodynamics, symptoms, and potentially LT outcomes; however, further study is needed to determine best treatment regimens, long-term outcomes on medical therapy, and role of LT. SUMMARY While HPS results in severe hypoxemia that is usually reversible by LT, PoPH patients develop progressive pulmonary hypertension that may improve with medical therapy.
Collapse
Affiliation(s)
- Kelley Weinfurtner
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Kimberly Forde
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| |
Collapse
|
|
13
|
Alvarado JC, Fuentes-Santamaría V, Juiz JM. Antioxidants and Vasodilators for the Treatment of Noise-Induced Hearing Loss: Are They Really Effective? Front Cell Neurosci 2020; 14:226. [PMID: 32792910 PMCID: PMC7387569 DOI: 10.3389/fncel.2020.00226] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 06/29/2020] [Indexed: 12/26/2022] Open
Abstract
We live in a world continuously immersed in noise, an environmental, recreational, and occupational factor present in almost every daily human activity. Exposure to high-level noise could affect the auditory function of individuals at any age, resulting in a condition called noise-induced hearing loss (NIHL). Given that by 2018, more than 400 million people worldwide were suffering from disabling hearing loss and that about one-third involved noise over-exposure, which represents more than 100 million people, this hearing impairment represents a serious health problem. As of today, there are no therapeutic measures available to treat NIHL. Conventional preventive measures, including public awareness and education and physical barriers to noise, do not seem to suffice, as the population is still being affected by damaging noise levels. Therefore, it is necessary to develop or test pharmacological agents that may prevent and/or diminish the impact of noise on hearing. Data availability about the pathophysiological processes involved in triggering NIHL has allowed researchers to use compounds, that could act as effective therapies, by targeting specific mechanisms such as the excess generation of free radicals and blood flow restriction to the cochlea. In this review, we summarize the advantages/disadvantages of these therapeutic agents, providing a critical view of whether they could be effective in the human clinic.
Collapse
Affiliation(s)
- Juan Carlos Alvarado
- Facultad de Medicina, Instituto de Investigación en Discapacidades, Neurológicas (IDINE), Universidad de Castilla-La Mancha, Albacete, Spain
| | - Verónica Fuentes-Santamaría
- Facultad de Medicina, Instituto de Investigación en Discapacidades, Neurológicas (IDINE), Universidad de Castilla-La Mancha, Albacete, Spain
| | - José M Juiz
- Facultad de Medicina, Instituto de Investigación en Discapacidades, Neurológicas (IDINE), Universidad de Castilla-La Mancha, Albacete, Spain.,Department of Otolaryngology, Hannover Medical School, NIFE-VIANNA, Cluster of Excellence Hearing4all-German Research Foundation, Hannover, Germany
| |
Collapse
|
|
14
|
Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU. Crit Care Med 2020; 48:e173-e191. [PMID: 32058387 DOI: 10.1097/ccm.0000000000004192] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
|
|
15
|
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.
Collapse
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
| |
Collapse
|
|
16
|
Wang Y, Ma K, Zhong A, Xiong Q, Chen J. Hepatopulmonary syndrome after radiofrequency ablation of recurrent intrahepatic cholangiocarcinoma: a case report. Onco Targets Ther 2019; 12:2431-2438. [PMID: 31040688 PMCID: PMC6452817 DOI: 10.2147/ott.s86702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background Radiofrequency ablation (RFA) is one of the definitive treatment modalities for liver cancer and has been increasingly used in the scenario of small-sized liver cancer. It is generally believed that RFA is minimally invasive and associated with a favorable safety profile in liver cancer patients. However, this interventional technique is subject to some morbidity in high-risk patients, such as those with complicating cirrhosis or a liver cancer located at a refractory segment. Methods Herein, we report the case of a middle-aged woman who developed acute liver failure with a complicating respiratory failure after RFA of recurrent intrahepatic cholangiocarcinoma. Results A diagnosis of hepatopulmonary syndrome was established. The patient was hospitalized in the intensive care unit for mechanical ventilation. Finally, the patient recovered from an eventful clinical course and survived free of recurrence until the last follow-up visit at 1 year after the discharge. Conclusion Our case report warns that hepatopulmonary syndrome, a less common morbidity secondary to liver cancer RFA, should require timely identification and appropriate management due to its life-threatening outcome.
Collapse
Affiliation(s)
- Yu Wang
- Institute of Hepatobiliary Surgery, Southwestern Hospital, People's Liberation Army Third Military Medical University, Chongqing, People's Republic of China,
| | - Kuansheng Ma
- Institute of Hepatobiliary Surgery, Southwestern Hospital, People's Liberation Army Third Military Medical University, Chongqing, People's Republic of China,
| | - Ai Zhong
- Institute of Hepatobiliary Surgery, Southwestern Hospital, People's Liberation Army Third Military Medical University, Chongqing, People's Republic of China,
| | - Qing Xiong
- Institute of Hepatobiliary Surgery, Southwestern Hospital, People's Liberation Army Third Military Medical University, Chongqing, People's Republic of China,
| | - Jian Chen
- Institute of Hepatobiliary Surgery, Southwestern Hospital, People's Liberation Army Third Military Medical University, Chongqing, People's Republic of China,
| |
Collapse
|
|
17
|
Riou M, Jutant EM, Mignard X, Canuet M, Humbert M, Sitbon O, Savale L, Montani D. Hépatopathies et maladies vasculaires pulmonaires. Rev Med Interne 2018; 39:925-934. [DOI: 10.1016/j.revmed.2018.07.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 07/23/2018] [Indexed: 12/26/2022]
|
|
18
|
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.
Collapse
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
| |
Collapse
|
|
19
|
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: 1775] [Impact Index Per Article: 253.6] [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]
|
|
20
|
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.
Collapse
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
| |
Collapse
|
|
21
|
Iqbal S, Smith KA, Khungar V. Hepatopulmonary Syndrome and Portopulmonary Hypertension: Implications for Liver Transplantation. Clin Chest Med 2017; 38:785-795. [PMID: 29128026 DOI: 10.1016/j.ccm.2017.08.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PoPH) represent serious pulmonary complications of advanced liver diseases. Orthotopic liver transplantation (OLT) is capable of completely resolving the underlying abnormalities associated with HPS. On the other hand, post-OLT response in patients with PoPH is less predictable, although heavily influenced by pre-OLT mean pulmonary arterial pressure. It remains the case that the opportunity to reverse 2 potentially fatal organ dysfunctions in the liver and the lung make HPS and PoPH more than worthy for further clinical investigations.
Collapse
Affiliation(s)
- Shaz Iqbal
- Department of Medicine, General Internal Medicine Division, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - Kerri Akaya Smith
- Department of Medicine, Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, 834 West Gates Building, Philadelphia, PA 19104, USA
| | - Vandana Khungar
- Department of Medicine, Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street 2 Dulles, Philadelphia, PA 19104, USA.
| |
Collapse
|
|
22
|
International Liver Transplant Society Practice Guidelines: Diagnosis and Management of Hepatopulmonary Syndrome and Portopulmonary Hypertension. Transplantation 2017; 100:1440-52. [PMID: 27326810 DOI: 10.1097/tp.0000000000001229] [Citation(s) in RCA: 291] [Impact Index Per Article: 36.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Two distinct pulmonary vascular disorders, hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH) may occur as a consequence of hepatic parenchymal or vascular abnormalities. HPS and POPH have major clinical implications for liver transplantation. A European Respiratory Society Task Force on Pulmonary-Hepatic Disorders convened in 2002 to standardize the diagnosis and guide management of these disorders. These International Liver Transplant Society diagnostic and management guidelines are based on that task force consensus and should continue to evolve as clinical experience dictates. Based on a review of over 1000 published HPS and POPH articles identified via a MEDLINE search (1985-2015), clinical guidelines were based on, selected single care reports, small series, registries, databases, and expert opinion. The paucity of randomized, controlled trials in either of these disorders was noted. Guidelines are presented in 5 parts; I. Definitions/Diagnostic criteria; II. Hepatopulmonary syndrome; III. Portopulmonary hypertension; IV. Implications for liver transplantation; and V. Suggestions for future clinical research.
Collapse
|
|
23
|
Puttappa A, Sheshadri K, Fabre A, Imberger G, Boylan J, Ryan S, Iqbal M, Conlon N. Prolonged Unexplained Hypoxemia as Initial Presentation of Cirrhosis: A Case Report. AMERICAN JOURNAL OF CASE REPORTS 2017; 18:1-6. [PMID: 28042141 PMCID: PMC5221740 DOI: 10.12659/ajcr.900530] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Patient: Male, 43 Final Diagnosis: Hepatopulmonary syndrome Symptoms: Dyspnea Medication: — Clinical Procedure: — Specialty: Gastroenterology and Hepatology
Collapse
Affiliation(s)
- Anand Puttappa
- Department of Anaesthesia and Intensive Care, St Vincent's University Hospital, Dublin, Ireland
| | - Kumaraswamy Sheshadri
- Department of Anaesthesia and Intensive Care, St Vincent's University Hospital, Dublin, Ireland
| | - Aurelie Fabre
- Department of Histopathology, St Vincent's University Hospital, Dublin, Ireland
| | - Georgina Imberger
- Department of Anaesthesia and Pain Medicine, Western Health, Melbourne, Australia
| | - John Boylan
- Department of Anaesthesia and Intensive Care, St Vincent's University Hospital, Dublin, Ireland
| | - Silke Ryan
- Department of Respiratory and Sleep Medicine, St Vincent's University Hospital, Dublin, Ireland
| | - Masood Iqbal
- Department of Hepatology, St Vincent's University Hospital, Dublin, Ireland
| | - Niamh Conlon
- Department of Anaesthesia and Intensive Care, St Vincent's University Hospital, Dublin, Ireland
| |
Collapse
|
|
24
|
CXCR2 is involved in pulmonary intravascular macrophage accumulation and angiogenesis in a rat model of hepatopulmonary syndrome. Clin Sci (Lond) 2016; 131:159-168. [DOI: 10.1042/cs20160593] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 11/03/2016] [Accepted: 11/22/2016] [Indexed: 12/29/2022]
Abstract
Hepatopulmonary syndrome (HPS) is a lung complication in various liver diseases, with high incidence, poor prognosis and no effective non-surgical treatments in patients with hepatocirrhosis. Therefore, assessing HPS pathogenesis to explore proper therapy strategies is clinically relevant. In the present study, male Sprague–Dawley rats underwent sham operation or common bile duct ligation (CBDL). Two weeks post-surgery, the following groups were set up for 2 weeks of treatment: sham + normal saline, CBDL + CXCR2 antagonist SB225002, CBDL + tumour necrosis factor α (TNF-α) antagonist PTX and CBDL + normal saline groups. Liver and lung tissues were collected after mean arterial pressure (MAP) and portal venous pressure (PVP) measurements. Haematoxylin and eosin (H&E) staining (lung) and Masson staining (liver) were performed for pathological analyses. Finally, pulmonary tissue RNA and total protein were assessed for target effectors. The mRNA and protein levels of CXCR2 were significantly increased in the pulmonary tissue of CBDL rats. What's more, CXCR2 inhibition by SB225002 reduced the expression of CD68 and von Willebrand factor (vWf) in CBDL rats. Importantly, CXCR2 inhibition suppressed the activation of Akt and extracellular signal-regulated kinase (ERK) in CBDL rats. Antagonization of TNF-α with PTX down-regulated the expression of CXCR2. During HPS pathogenesis in rats, CXCR2 might be involved in the accumulation of pulmonary intravascular macrophages and angiogenesis, possibly by activating Akt and ERK, with additional regulation by TNF-α that enhanced pulmonary angiogenesis by directly acting on the pulmonary tissue. Finally, the present study may provide novel targets for the treatment of HPS.
Collapse
|
|
25
|
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.
Collapse
|
|
26
|
CT Scan Does Not Differentiate Patients with Hepatopulmonary Syndrome from Other Patients with Liver Disease. PLoS One 2016; 11:e0158637. [PMID: 27384058 PMCID: PMC4934684 DOI: 10.1371/journal.pone.0158637] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 06/20/2016] [Indexed: 01/14/2023] Open
Abstract
Background Hepatopulmonary syndrome (HPS) is defined by liver dysfunction, intrapulmonary vascular dilatations, and impaired oxygenation. The gold standard for detection of intrapulmonary vascular dilatations in HPS is contrast echocardiography. However, two small studies have suggested that patients with HPS have larger segmental pulmonary arterial diameters than both normal subjects and normoxemic subjects with cirrhosis, when measured by CT. We sought to compare CT imaging-based pulmonary vasodilatation in patients with HPS, patients with liver dysfunction without HPS, and matching controls on CT imaging. Methods We performed a retrospective cohort study at two quaternary care Canadian HPS centers. We analyzed CT thorax scans in 23 patients with HPS, 29 patients with liver dysfunction without HPS, and 52 gender- and age-matched controls. We measured the artery-bronchus ratios (ABRs) in upper and lower lung zones, calculated the “delta ABR” by subtracting the upper from the lower ABR, compared these measurements between groups, and correlated them with clinically relevant parameters (partial pressure of arterial oxygen, alveolar-arterial oxygen gradient, macroaggregated albumin shunt fraction, and diffusion capacity). We repeated measurements in patients with post-transplant CTs. Results Patients had significantly larger lower zone ABRs and delta ABRs than controls (1.20 +/- 0.19 versus 0.98 +/- 0.10, p<0.01; and 0.12 +/- 0.17 versus -0.06 +/- 0.10, p<0.01, respectively). However, there were no significant differences between liver disease patients with and without HPS, nor any significant correlations between CT measurements and clinically relevant parameters. There were no significant changes in ABRs after liver transplantation (14 patients). Conclusions Basilar segmental artery-bronchus ratios are larger in patients with liver disease than in normal controls, but this vasodilatation is no more severe in patients with HPS. CT does not distinguish patients with HPS from those with uncomplicated liver disease.
Collapse
|
|
27
|
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.
Collapse
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:
| |
Collapse
|
|
28
|
Goldberg DS, Fallon MB. The Art and Science of Diagnosing and Treating Lung and Heart Disease Secondary to Liver Disease. Clin Gastroenterol Hepatol 2015; 13:2118-27. [PMID: 25934564 PMCID: PMC4618073 DOI: 10.1016/j.cgh.2015.04.024] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 04/13/2015] [Accepted: 04/14/2015] [Indexed: 02/07/2023]
Abstract
Patients with chronic liver disease are at risk of extrahepatic complications related to cirrhosis and portal hypertension, as well as organ-specific complications of certain liver diseases. These complications can compromise quality of life, while also increasing morbidity and mortality before and after liver transplantation. Patients with chronic liver disease are at risk for pulmonary complications of hepatopulmonary syndrome and portopulmonary syndrome; the cardiac complication fall under the general concept of cirrhotic cardiomyopathy, which can affect systolic and diastolic function, as well as cardiac conduction. In addition, patients with certain diseases are at risk of lung and/or cardiac complications that are specific to the primary disease (ie, emphysema in α-1-antitrypsin deficiency) or occur with increased incidence in certain conditions (ie, ischemic heart disease associated with nonalcoholic steatohepatitis). This article focuses on the epidemiology, clinical presentation, pathogenesis, treatment options, and role of transplantation for lung and heart diseases secondary to liver disease, while also highlighting select liver diseases that directly affect the lungs and heart.
Collapse
Affiliation(s)
- David S Goldberg
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Leonard Davis Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
| | - Michael B Fallon
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas
| |
Collapse
|
|
29
|
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.
Collapse
Affiliation(s)
- Yong Lv
- Department of Liver Disease, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China,
| | | |
Collapse
|
|
30
|
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]
|
|
31
|
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: 61] [Impact Index Per Article: 6.1] [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.
Collapse
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
| |
Collapse
|
|
32
|
Grady K, Gowda S, Kingah P, Soubani AO. Coil embolization of pulmonary arteries as a palliative treatment of diffuse type I hepatopulmonary syndrome. Respir Care 2015; 60:e20-e25. [PMID: 25185147 DOI: 10.4187/respcare.03198] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Hepatopulmonary syndrome is a serious complication of liver disease. Type I hepatopulmonary syndrome is associated with diffuse dilatation of the pulmonary vasculature, leading to severe hypoxemia. Liver transplantation is the treatment of choice for this condition. There are limited options for those who are not candidates for liver transplantation. We present the case of a patient who presented with severe hypoxemia requiring FIO2 of 0.95 with PaO2 of 59 mm Hg. Workup revealed 33% intrapulmonary right-to-left shunt. A pulmonary angiogram showed diffuse dilatation of the pulmonary arteries, especially in the lower lobes. The patient was diagnosed with type I hepatopulmonary syndrome. He was not a candidate for liver transplantation. The patient underwent sequential coil embolizations of the lower lobe pulmonary arteries. He was discharged home on 2 L of supplemental oxygen. This case demonstrates that coil embolization of dilated pulmonary arteries is a potential palliative treatment for patients with diffuse type I hepatopulmonary syndrome.
Collapse
Affiliation(s)
| | - Srinath Gowda
- Division of Pediatric Cardiology, Wayne State University School of Medicine, Detroit, Michigan
| | - Pascal Kingah
- Division of Pulmonary & Critical Care and Sleep Medicine
| | | |
Collapse
|
|
33
|
Fuhrmann V, Drolz A, Rutter K, Horvatits T. HPS: Diagnosis, clinical features, and medical therapy. Clin Liver Dis (Hoboken) 2014; 4:46-49. [PMID: 30992920 PMCID: PMC6448732 DOI: 10.1002/cld.402] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Revised: 05/26/2014] [Accepted: 06/20/2014] [Indexed: 02/04/2023] Open
Affiliation(s)
- Valentin Fuhrmann
- Martinistraβe 52, University Medical Center Hamburg Eppendorf, Hamburg, Germany. Phone: +49‐40‐7410‐0.
| | - Andreas Drolz
- Martinistraβe 52, University Medical Center Hamburg Eppendorf, Hamburg, Germany. Phone: +49‐40‐7410‐0.
| | - Karoline Rutter
- Martinistraβe 52, University Medical Center Hamburg Eppendorf, Hamburg, Germany. Phone: +49‐40‐7410‐0.
| | - Thomas Horvatits
- Martinistraβe 52, University Medical Center Hamburg Eppendorf, Hamburg, Germany. Phone: +49‐40‐7410‐0.
| |
Collapse
|
|
34
|
Aldenkortt F, Aldenkortt M, Caviezel L, Waeber JL, Weber A, Schiffer E. Portopulmonary hypertension and hepatopulmonary syndrome. World J Gastroenterol 2014; 20:8072-8081. [PMID: 25009379 PMCID: PMC4081678 DOI: 10.3748/wjg.v20.i25.8072] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
Portopulmonary hypertension (POPH) and hepatopulmonary syndrome (HPS) are two frequent complications of liver disease, with prevalence among liver transplant candidates of 6% and 10%, respectively. Both conditions result from a lack of hepatic clearance of vasoactive substances produced in the splanchnic territory. Subsequently, these substances cause mainly pulmonary vascular remodeling and some degree of vasoconstriction in POPH with resulting elevated pulmonary pressure and right ventricular dysfunction. In HPS the vasoactive mediators cause intrapulmonary shunts with hypoxemia. Medical treatment is disappointing overall. Whereas liver transplantation (LT) results in the disappearance of HPS within six to twelve months, its effect on POPH is highly unpredictable. Modern strategies in managing HPS and POPH rely on a thorough screening and grading of the disease’s severity, in order to tailor the appropriate therapy and select only the patients who will benefit from LT. The anesthesiologist plays a central role in managing these high-risk patients. Indeed, the important hemodynamic and respiratory modifications of the perioperative period must be avoided through continuation of the preoperatively initiated drugs, appropriate intraoperative monitoring and proper hemodynamic and respiratory therapies.
Collapse
|
|
35
|
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.
Collapse
|
|
36
|
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.
Collapse
|
|
37
|
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.
Collapse
|
|
38
|
Horvatits T, Drolz A, Rutter K, Kluge S, Fuhrmann V. [Pulmonary complications in liver diseases]. Med Klin Intensivmed Notfmed 2014; 109:235-9. [PMID: 24763525 DOI: 10.1007/s00063-013-0319-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Accepted: 03/19/2014] [Indexed: 01/13/2023]
Abstract
Pulmonary-hepatic vascular disorders are frequent complications in patients with portal hypertension and cirrhosis. Hepatopulmonary syndrome (HPS), portopulmonary hypertension (POPH), and hepatic hydrothorax are relevant disease entities in these patients. HPS occurs in up to 30 % of patients with cirrhosis and is associated with a more than 2-fold increased mortality. The diagnosis of HPS should be established early by arterial blood gas analysis and contrast-enhanced echocardiography, whereas POPH is diagnosed by the presence of pulmonary arterial hypertension evaluated via right heart catheterization and the presence of portal hypertension. Therapeutic options include initiation of long-term oxygen therapy and liver transplantation in patients with severe HPS. Patients with POPH should receive targeted medical therapies with endothelin receptor antagonists, phosphodiesterase-5 inhibitors and/or prostanoids. In contrast, β-blockers should be avoided. This review summarizes current knowledge regarding pulmonary-hepatic vascular disorders, with a focus on HPS.
Collapse
Affiliation(s)
- T Horvatits
- Klinik für Intensivmedizin, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Deutschland
| | | | | | | | | |
Collapse
|
|
39
|
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.
Collapse
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:
| |
Collapse
|
|
40
|
Tumgor G. Cirrhosis and hepatopulmonary syndrome. World J Gastroenterol 2014; 20:2586-2594. [PMID: 24627594 PMCID: PMC3949267 DOI: 10.3748/wjg.v20.i10.2586] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 01/05/2014] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatopulmonary syndrome (HPS) is characterized as a triad: liver disease, intrapulmonary vascular dilatation and arterial hypoxemia. HPS is reported to be present in 4% to 32% of adult patients with end-stage liver disease and in 9%-20% of children. The pathogenesis of HPS has not been clearly identified. Portal hypertension causes impairment in the perfusion of the bowel and increases the enteral translocation of Gram (-) bacteria and endotoxins. This stimulates the release of vasoactive mediators, such as tumor necrosis factor-alpha, heme oxygenase-derived carbon monoxide and nitric oxide. Genetic alterations have not been associated with this syndrome yet; however, cytokines and chemokines have been suggested to play a role. Recently, it was reported that cumulated monocytes lead to the activation of vascular endothelial growth factor-dependent signaling pathways and pulmonary angiogenesis, which plays an important role in HPS pathogenesis. At present, the most effective and only radical treatment is a liver transplant (LT). Cirrhotic patients who are on the waiting list for an LT have a shorter survival period if they develop HPS. Therefore, it is suggested that all cirrhotic cases should be followed closely for HPS and they should have priority in the waiting list.
Collapse
|
|
41
|
Abstract
BACKGROUND In a previous small retrospective study, the authors reported that hepatopulmonary syndrome was less common among liver transplant candidates at high-altitude centres compared with low-altitude centres. OBJECTIVE To further explore the relationship between hepatopulmonary syndrome and altitude of residence in a larger patient cohort. METHODS A cohort of 65,264 liver transplant candidates in the Organ Procurement and Transplantation Network liver database between 1988 and 2006 was analyzed. Hepatopulmonary syndrome diagnosis was determined during a comprehensive evaluation at a liver transplant centre by physicians who were experienced in the diagnosis and treatment of hepatopulmonary syndrome. The altitude of residence was determined for each patient by assigning the mean altitude of the zip code of residence at the time of entry on the wait list. Mean zip code elevation was calculated using the National Elevation Dataset of the United States Geological Survey, which provides exact elevation measurements across the entire country. RESULTS Hepatopulmonary syndrome was significantly less common at higher resident altitudes (P=0.015). After adjusting for age, sex and Model for End-Stage Liver Disease score, there was a 46% decrease in the odds of hepatopulmonary syndrome with every increase of 1000 m of resident elevation (OR 0.54 [95% CI 0.33 to 0.89]). CONCLUSION There was a negative association between altitude and hepatopulmonary syndrome. One plausible explanation is that the lower ambient oxygen found at higher elevation leads to pulmonary vasoconstriction, which mitigates the primary physiological lesion of hepatopulmonary syndrome, namely, pulmonary vasodilation.
Collapse
|
|
42
|
Chen Y, Yi B, Wang Z, Gu J, Li Y, Cui J, Lu K. Paxillin suppresses the proliferation of HPS rat serum treated PASMCs by up-regulating the expression of cytoskeletal proteins. MOLECULAR BIOSYSTEMS 2014; 10:759-66. [PMID: 24457422 DOI: 10.1039/c3mb70391f] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Hepatopulmonary syndrome (HPS) is a triad of advanced liver disease, intrapulmonary vasodilatation (IPVD), and arterial hypoxemia. The arterial hypoxemia induces pulmonary vascular remodelling (PVR). In recent studies, the role of the proliferation of pulmonary artery smooth muscle cells (PASMCs) in PVR associated with HPS has been established; the changes in cytoskeletal proteins play an essential role in the proliferation of PASMCs. Little is known about the relevance of cytoskeletal protein expression or the molecular mechanisms of PVR associated with HPS. In addition, it has been identified that paxillin could influence the cytoskeletal protein expression by some important signaling pathways in many diseases, including lung cancer and liver cancer. In this study, we found that HPS rat serum from a common bile duct ligation (CBDL) rat model decreased the expression of cytoskeletal proteins (α-actin, α-tubulin, and destrin) and enhanced the expression levels of paxillin mRNA and protein in PASMCs. After silencing paxillin with siRNA, we found that the down-regulation of cytoskeletal protein expression, induced by the HPS rat serum, was reversed. Additionally, we reported that HPS rat serum improved the proliferation of PASMCs and down-regulation of paxillin could significantly inhibit this variation. These findings suggest that the up-regulation of cytoskeletal protein expression, induced by the paxillin, may cause the dysregulation of PASMC proliferation as well as play a fundamental role in PVR associated with HPS. In conclusion, down-regulation of paxillin by siRNA results in the inhibition of the dysregulation of cytoskeletal proteins and proliferation of PASMCs, suggesting a potential therapeutic effect on PVR associated with HPS.
Collapse
Affiliation(s)
- Yang Chen
- Department of Anesthesia, Southwest Hospital, the Third Military Medical University, Chongqing 400038, China.
| | | | | | | | | | | | | |
Collapse
|
|
43
|
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]
|
|
44
|
Eshraghian A, Kamyab AA, Yoon SK. Pharmacological treatment for hepatopulmonary syndrome. BIOMED RESEARCH INTERNATIONAL 2013; 2013:670139. [PMID: 24102057 PMCID: PMC3786536 DOI: 10.1155/2013/670139] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 07/30/2013] [Accepted: 08/12/2013] [Indexed: 12/12/2022]
Abstract
AIM Hepatopulmonary syndrome is a pulmonary dysfunction in the context of liver cirrhosis characterized by arterial deoxygenation. Affected patients have increased morbidity and mortality, and many of them expire before undergoing liver transplantation. Therefore, finding medical therapy as a bridge to transplantation or as a final treatment is necessary. In this study, we aimed to review the current literature about pharmacological options available for treatment of hepatopulmonary syndrome. METHODS A PubMED and Scopus search was conducted in January 2013 on the English literature published in any time period to find human and animal studies reporting pharmacological therapy of hepatopulmonary syndrome. RESULTS Out of 451 studies, 29 relevant articles were included. The number of patients, type, dose, duration, and mechanism of drugs in these studies was extracted and summarized separately. Most of pharmacologic agents act through inhibition of nitric oxide synthase and reduction in nitric oxide production, inactivation of endothelin-1, and treatment of bacterial translocation and pulmonary angiogenesis. CONCLUSION Several drugs have been applied for the treatment of HPS with conflicting results. However, no large randomized trial has been conducted probably due to low number of patients. Multicentered clinical trials are necessary to investigate these drugs.
Collapse
Affiliation(s)
- Ahad Eshraghian
- Department of Internal Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir A'lam Kamyab
- Department of Internal Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seung Kew Yoon
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kangnam St. Mary Hospital, Catholic University Medical College, Seoul, Republic of Korea
| |
Collapse
|
|
45
|
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]
|
|
46
|
Porres-Aguilar M, Gallegos-Orozco JF, Garcia H, Aguirre J, Macias-Rodriguez RU, Torre-Delgadillo A. Pulmonary vascular complications in portal hypertension and liver disease: a concise review. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2013; 78:35-44. [PMID: 23369639 DOI: 10.1016/j.rgmx.2012.10.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2012] [Accepted: 10/19/2012] [Indexed: 11/30/2022]
Abstract
Chronic liver disease and/or portal hypertension may be associated with one of the two pulmonary vascular complications: portopulmonary hypertension and hepatopulmonary syndrome. These pulmonary vascular disorders are notoriously underdiagnosed; however, they have a substantial negative impact on survival and require special attention in order to understand their diagnostic approach and to select the best therapeutic options. Portopulmonary hypertension results from excessive vasoconstriction, vascular remodeling, and proliferative and thrombotic events within the pulmonary circulation that lead to progressive right ventricular failure and ultimately to death. On the other hand, abnormal intrapulmonary vascular dilations, profound hypoxemia, and a wide alveolar-arterial gradient are the hallmarks of the hepatopulmonary syndrome, resulting in difficult-to-treat hypoxemia. The aim of this review is to summarize the latest pathophysiologic concepts, diagnostic approach, therapy, and prognosis of portopulmonary hypertension and hepatopulmonary syndrome, as well as to discuss the role of liver transplantation as a definitive therapy in selected patients with these conditions.
Collapse
Affiliation(s)
- M Porres-Aguilar
- Department of Internal Medicine, Division of Hospital Medicine, Texas Tech University Health Sciences Center/Paul L. Foster School of Medicine, El Paso, TX, USA.
| | | | | | | | | | | |
Collapse
|
|
47
|
Grace JA, Angus PW. Hepatopulmonary syndrome: update on recent advances in pathophysiology, investigation, and treatment. J Gastroenterol Hepatol 2013. [PMID: 23190201 DOI: 10.1111/jgh.12061] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatopulmonary syndrome (HPS) is an important cause of dyspnea and hypoxia in the setting of liver disease, occurring in 10-30% of patients with cirrhosis. It is due to vasodilation and angiogenesis in the pulmonary vascular bed, which leads to ventilation-perfusion mismatching, diffusion limitation to oxygen exchange, and arteriovenous shunting. There is evidence, primarily from animal studies, that vasodilation is mediated by a number of endogenous vasoactive molecules, including endothelin-1 and nitric oxide (NO). In experimental HPS, liver injury stimulates release of endothelin-1 and results in increased expression of ET(B) receptors on pulmonary endothelial cells, leading to upregulation of endothelial NO synthase (eNOS) and subsequent increased production of NO, which causes vasodilation. In addition, increased phagocytosis of bacterial endotoxin in the lung not only promotes stimulation of inducible NO synthase, which increases NO production, but also contributes to intrapulmonary accumulation of monocytes, which may stimulate angiogenesis via vascular endothelial growth factor pathway. Despite these insights into the pathogenesis of experimental HPS, there is no established medical therapy, and liver transplantation remains the main treatment for symptomatic HPS, although selected patients may benefit from other surgical or radiological interventions. In this review, we focus on recent advances in our understanding of the pathophysiology of HPS, and discuss current approaches to the investigation and treatment of this condition.
Collapse
Affiliation(s)
- Josephine A Grace
- Department of Medicine, Austin Health, The University of Melbourne, Melbourne, Victoria, Australia.
| | | |
Collapse
|
|
48
|
Fritz JS, Fallon MB, Kawut SM. Pulmonary vascular complications of liver disease. Am J Respir Crit Care Med 2012; 187:133-43. [PMID: 23155142 DOI: 10.1164/rccm.201209-1583ci] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hepatopulmonary syndrome and portopulmonary hypertension are two pulmonary vascular complications of liver disease. The pathophysiology underlying each disorder is distinct, but patients with either condition may be limited by dyspnea. A careful evaluation of concomitant symptoms, the physical examination, pulmonary function testing and arterial blood gas analysis, and echocardiographic, imaging, and hemodynamic studies is crucial to establishing (and distinguishing) these diagnoses. Our understanding of the pathobiology, natural history, and treatment of these disorders has advanced considerably over the past decade; however, the presence of either still increases the risk of morbidity and mortality in patients with underlying liver disease. There is no effective medical treatment for hepatopulmonary syndrome. Although liver transplantation can resolve hepatopulmonary syndrome, there appears to be worse survival even with transplantation. Liver transplantation poses a very high risk of death in those with significant portopulmonary hypertension, where targeted medical therapies may improve functional status and allow successful transplantation in a small number of select patients.
Collapse
Affiliation(s)
- Jason S Fritz
- Department of Medicine, M.S., Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | | | | |
Collapse
|
|
49
|
Kianifar HR, Khalesi M, Mahmoodi E, Afzal Aghaei M. Pentoxifylline in hepatopulmonary syndrome. World J Gastroenterol 2012; 18:4912-6. [PMID: 23002364 PMCID: PMC3447274 DOI: 10.3748/wjg.v18.i35.4912] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2011] [Revised: 05/10/2012] [Accepted: 06/08/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the effects of pentoxifylline (PTX) on clinical manifestations and evaluate arterial blood gas data in hepatopulmonary syndrome (HPS) in children.
METHODS: In a pilot study of 10 children with chronic liver disease, who had HPS, 20 mg/kg/d PTX was administered for 3 mo. Clinical data and arterial blood gas parameters were evaluated at baseline, the end of the treatment period, and 3 mo after drug discontinuation.
RESULTS: Six patients could tolerate PTX, while four patients experienced complications. Among patients who could tolerate PTX, there was a significant increase in arterial oxygen pressure (PaO2) (P = 0.02) and oxygen saturation (SaO2) (P = 0.04) and alveolar-arterial oxygen gradient (P = 0.02) after 3 mo of treatment. Significant decreases in PaO2 (P = 0.02) and alveolar-arterial oxygen gradient (P = 0.02) were also seen after drug discontinuation.
CONCLUSION: PTX may improve PaO2, SaO2 and alveolar-arterial oxygen gradient in the early stage of HPS.
Collapse
|
|
50
|
Abstract
Hepatopulmonary syndrome (HPS) is a serious vascular complication of liver disease that occurs in 5-32% of patients with cirrhosis. The presence of HPS markedly increases mortality. No effective medical therapies are currently available and liver transplantation is the only established treatment option for HPS. The definition and diagnosis of HPS are established by the presence of a triad of liver disease with intrapulmonary vascular dilation that causes abnormal arterial gas exchange. Experimental biliary cirrhosis induced by common bile duct ligation in the rat reproduces the pulmonary vascular and gas exchange abnormalities of human HPS and serves as a pertinent animal model. Pulmonary microvascular dilation and angiogenesis are two central pathogenic features that drive abnormal pulmonary gas exchange in experimental HPS, and thus might underlie HPS in humans. Defining the mechanisms involved in the microvascular alterations of HPS has the potential to lead to effective medical therapies. This Review focuses on the current understanding of the pathogenesis, clinical features and management of HPS.
Collapse
Affiliation(s)
- Junlan Zhang
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, 6431 Fannin Street, MSB 4.234, Houston, TX 77030-1501, USA
| | | |
Collapse
|