|
1
|
Pinter M, Fulgenzi CAM, Pinato DJ, Scheiner B. Systemic treatment in patients with hepatocellular carcinoma and advanced liver dysfunction. Gut 2025:gutjnl-2025-334928. [PMID: 40301119 DOI: 10.1136/gutjnl-2025-334928] [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: 01/27/2025] [Accepted: 04/12/2025] [Indexed: 05/01/2025]
Abstract
Systemic therapy represents the standard of care treatment for patients with advanced hepatocellular carcinoma (HCC). Given the increased risk of death from cirrhosis-related complications in patients with advanced liver dysfunction, pivotal phase III trials traditionally limited inclusion to patients with Child-Pugh class A, where death is more likely to be attributed to HCC progression. Therefore, Western guidelines recommend the use of systemic therapies primarily in patients with preserved liver function. However, patients with HCC and Child-Pugh class B are commonly encountered in clinical practice, but due to limited prospective evidence, there is no clear guidance on their optimal management.In this recent advances article, we discuss how the clinical course of cirrhosis can affect eligibility to treatment in the modern era of systemic therapy for HCC, elaborate on strategies to improve liver function in HCC patients by targeting cirrhosis-related and tumour-related factors and summarise the current literature on systemic therapy in HCC patients with Child-Pugh class B. Based on this information, we finally propose a clinical algorithm on how to systematically approach patients with HCC and advanced liver dysfunction in clinical practice.
Collapse
Affiliation(s)
- Matthias Pinter
- Division of Gastroenterology & Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Claudia A M Fulgenzi
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - David J Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Department of Translational Medicine, Division of Oncology, University of Piemonte Orientale, Novara, Italy
| | - Bernhard Scheiner
- Division of Gastroenterology & Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| |
Collapse
|
|
2
|
Ververeli CL, Dimitroglou Y, Soulaidopoulos S, Cholongitas E, Aggeli C, Tsioufis K, Tousoulis D. Cardiac Remodeling and Arrhythmic Burden in Pre-Transplant Cirrhotic Patients: Pathophysiological Mechanisms and Management Strategies. Biomedicines 2025; 13:812. [PMID: 40299454 PMCID: PMC12025098 DOI: 10.3390/biomedicines13040812] [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] [Received: 02/09/2025] [Revised: 03/22/2025] [Accepted: 03/25/2025] [Indexed: 04/30/2025] Open
Abstract
Background: Chronic liver disease (CLD) and cirrhosis contribute to approximately 2 million deaths annually, with primary causes including alcohol-related liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and chronic hepatitis B and C infections. Among these, MASLD has emerged as a significant global health concern, closely linked to metabolic disorders and a leading cause of liver failure and transplantation. Objective: This review aims to highlight the interplay between cirrhosis and cardiac dysfunction, emphasizing the pathophysiology, diagnostic criteria, and management of cirrhotic cardiomyopathy (CCM). Methods: A comprehensive literature review was conducted to evaluate the hemodynamic and structural cardiac alterations in cirrhosis. Results: Cirrhosis leads to portal hypertension and systemic inflammation, contributing to CCM, which manifests as subclinical cardiac dysfunction, impaired contractility, and electrophysiological abnormalities. Structural changes, such as increased left ventricular mass, myocardial fibrosis, and ion channel dysfunction, further impair cardiac function. Vasodilation in the splanchnic circulation reduces peripheral resistance, triggering compensatory tachycardia, while the activation of the renin-angiotensin-aldosterone system (RAAS) promotes fluid retention and increases cardiac preload. Chronic inflammation and endotoxemia exacerbate myocardial dysfunction. The 2005 World Congress of Gastroenterology (WCG) and the 2019 Cirrhotic Cardiomyopathy Consortium (CCC) criteria provide updated diagnostic frameworks that incorporate global longitudinal strain (GLS) and tissue Doppler imaging (TDI). Prolonged QT intervals and arrhythmias are frequently observed. Managing heart failure in cirrhotic patients remains complex due to intolerance to afterload-reducing agents, and beta-blockers require careful use due to potential systemic hypotension. The interaction between CCM and major interventions, such as transjugular intrahepatic portosystemic shunt (TIPS) and orthotopic liver transplantation (OLT), highlights the critical need for thorough preoperative cardiac evaluation and vigilant postoperative monitoring. Conclusions: CCM is a frequently underdiagnosed yet significant complication of cirrhosis, impacting prognosis, particularly post-liver transplantation. Early identification using echocardiography and thorough evaluations of arrhythmia risk in cirrhotic patients are critical for optimizing management strategies. Future research should focus on targeted therapeutic approaches to mitigate the cardiac burden in cirrhotic patients and improve clinical outcomes.
Collapse
Affiliation(s)
- Charilila-Loukia Ververeli
- 1st Department of Cardiology, Hippokrateio General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.-L.V.); (S.S.); (C.A.); (K.T.); (D.T.)
| | - Yannis Dimitroglou
- 1st Department of Cardiology, Hippokrateio General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.-L.V.); (S.S.); (C.A.); (K.T.); (D.T.)
| | - Stergios Soulaidopoulos
- 1st Department of Cardiology, Hippokrateio General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.-L.V.); (S.S.); (C.A.); (K.T.); (D.T.)
| | - Evangelos Cholongitas
- 1st Department of Internal Medicine, Laiko General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Constantina Aggeli
- 1st Department of Cardiology, Hippokrateio General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.-L.V.); (S.S.); (C.A.); (K.T.); (D.T.)
| | - Konstantinos Tsioufis
- 1st Department of Cardiology, Hippokrateio General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.-L.V.); (S.S.); (C.A.); (K.T.); (D.T.)
| | - Dimitris Tousoulis
- 1st Department of Cardiology, Hippokrateio General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.-L.V.); (S.S.); (C.A.); (K.T.); (D.T.)
| |
Collapse
|
|
3
|
Zeng Y, Fu BM. Angiogenesis and Microvascular Permeability. Cold Spring Harb Perspect Med 2025; 15:a041163. [PMID: 38692737 PMCID: PMC11694756 DOI: 10.1101/cshperspect.a041163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2024]
Abstract
Angiogenesis, the formation of new blood microvessels, is a necessary physiological process for tissue generation and repair. Sufficient blood supply to the tissue is dependent on microvascular density, while the material exchange between the circulating blood and the surrounding tissue is controlled by microvascular permeability. We thus begin this article by reviewing the key signaling factors, particularly vascular endothelial growth factor (VEGF), which regulates both angiogenesis and microvascular permeability. We then review the role of angiogenesis in tissue growth (bone regeneration) and wound healing. Finally, we review angiogenesis as a pathological process in tumorigenesis, intraplaque hemorrhage, cerebral microhemorrhage, pulmonary fibrosis, and hepatic fibrosis. Since the glycocalyx is important for both angiogenesis and microvascular permeability, we highlight the role of the glycocalyx in regulating the interaction between tumor cells and endothelial cells (ECs) and VEGF-containing exosome release and uptake by tumor-associated ECs, all of which contribute to tumorigenesis and metastasis.
Collapse
Affiliation(s)
- Ye Zeng
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Bingmei M Fu
- Department of Biomedical Engineering, The City College of the City University of New York, New York, New York 10031, USA
| |
Collapse
|
|
4
|
Galasso L, Cerrito L, Termite F, Mignini I, Esposto G, Borriello R, Ainora ME, Gasbarrini A, Zocco MA. The Molecular Mechanisms of Portal Vein Thrombosis in Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:3247. [PMID: 39409869 PMCID: PMC11482560 DOI: 10.3390/cancers16193247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 09/21/2024] [Accepted: 09/22/2024] [Indexed: 10/19/2024] Open
Abstract
Hepatocellular carcinoma (HCC) represents the sixth most diagnosed cancer worldwide and is the second leading cause of cancer-related death in the world. The association of HCC and portal vein thrombosis (PVT) represents an advanced stage of the tumor. PVT has a prevalence of about 25-50% in HCC, determining poor prognosis and a remarkable reduction in therapeutic perspectives in these patients, leading to severe complications such as ascites, metastasis, an increase in portal hypertension and potentially fatal gastrointestinal bleeding. The aim of this review is to evaluate the molecular mechanisms that are at the basis of PVT development, trying to evaluate possible strategies in the early detection of patients at high risk of PVT.
Collapse
Affiliation(s)
- Linda Galasso
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (M.E.A.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Lucia Cerrito
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (M.E.A.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Fabrizio Termite
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (M.E.A.)
| | - Irene Mignini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (M.E.A.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Giorgio Esposto
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (M.E.A.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Raffaele Borriello
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (M.E.A.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Elena Ainora
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (M.E.A.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (M.E.A.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Assunta Zocco
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (M.E.A.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| |
Collapse
|
|
5
|
Pun C, Huang HC, Chang CC, Hsu SJ, Chuang CL, Huang YH, Hou MC, Lee FY. Low-dose alcohol exacerbates hyperdynamic circulation and shunting in non-alcoholic cirrhotic rats. Biosci Rep 2024; 44:BSR20240354. [PMID: 38967060 PMCID: PMC11263042 DOI: 10.1042/bsr20240354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 06/18/2024] [Accepted: 07/02/2024] [Indexed: 07/06/2024] Open
Abstract
BACKGROUND Portal hypertension affects hepatic, splanchnic and portosystemic collateral systems. Although alcohol is a well-known risk factor for liver cirrhosis, it also affects vascular contractility. However, the relevant effects on portal hypertension have not been evaluated in non-alcoholic cirrhosis. The present study aimed to investigate the impacts of low-dose alcohol on portal hypertension-related derangements in non-alcoholic cirrhotic rats. METHODS Sprague-Dawley rats received bile duct ligation to induce cirrhosis or sham operation as controls. The chronic or acute effects of low-dose alcohol (2.4 g/kg/day, oral gavage, approximately 1.3 drinks/day in humans) were evaluated. RESULTS The chronic administration of low-dose alcohol did not precipitate liver fibrosis in the sham or cirrhotic rats; however, it significantly increased splanchnic blood inflow (P=0.034) and portosystemic collaterals (P=0.001). Mesenteric angiogenesis and pro-angiogenic proteins were up-regulated in the alcohol-treated cirrhotic rats, and poorer collateral vasoresponsiveness to vasoconstrictors (P<0.001) was noted. Consistently, acute alcohol administration reduced splenorenal shunt resistance. Collateral vasoresponsiveness to vasoconstrictors also significantly decreased (P=0.003). CONCLUSIONS In non-alcoholic cirrhosis rats, a single dose of alcohol adversely affected portosystemic collateral vessels due to vasodilatation. Long-term alcohol use precipitated splanchnic hyperdynamic circulation, in which mesenteric angiogenesis played a role. Further studies are warranted to evaluate the benefits of avoiding low-dose alcohol consumption in patients with non-alcoholic cirrhosis.
Collapse
Affiliation(s)
- Chon Kit Pun
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hui-Chun Huang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ching-Chih Chang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Holistic and Multidisciplinary Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shao-Jung Hsu
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chiao-Lin Chuang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Chih Hou
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Fa-Yauh Lee
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| |
Collapse
|
|
6
|
Dong W, Chu HB. Role of splenomegaly in surgical treatment of portal hypertension. WORLD CHINESE JOURNAL OF DIGESTOLOGY 2024; 32:248-253. [DOI: 10.11569/wcjd.v32.i4.248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/28/2024]
|
|
7
|
Kumar MS. Paneth cell: The missing link between obesity, MASH and portal hypertension. Clin Res Hepatol Gastroenterol 2024; 48:102259. [PMID: 38070827 DOI: 10.1016/j.clinre.2023.102259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 11/26/2023] [Accepted: 11/30/2023] [Indexed: 12/18/2023]
Abstract
Obesity is a global health crisis, with its prevalence steadily rising over the past few decades. One concerning consequence of obesity is its association with metabolic associated steatohepatitis [MASH], portal hypertension and liver cirrhosis. Cirrhosis is irreversible, but stages of liver disease before the development of cirrhosis are reversible with appropriate interventions. Studies have brought into light new entities that influences the pathophysiology of portal hypertension. This review provides evidence supporting that, Paneth cells[PCs] in the intestinal epithelium, which remained enigmatic for a century, are the maneuverer of pathophysiology of portal hypertension and obesity. PC dysfunction can cause perturbation of the intestinal microbiota and changes in intestinal permeability, which are the potential triggers of systemic inflammation. Thus, it can offer unique opportunities to understand the pathophysiology of portal hypertension for intervention strategies.
Collapse
Affiliation(s)
- Minu Sajeev Kumar
- Department of Gastroenterology, Government Medical College, Thiruvanathapuram, India.
| |
Collapse
|
|
8
|
Yu F, Zhu Y, Li N, Fu HF, Jiang Z, Zhang XY, Zeng L, Hu XY. Gastro‑oesophageal reflux disease in liver cirrhosis: Possible pathogenesis and clinical intervention (Review). Exp Ther Med 2023; 26:414. [PMID: 37559931 PMCID: PMC10407984 DOI: 10.3892/etm.2023.12113] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 03/31/2023] [Indexed: 08/11/2023] Open
Abstract
Oesophageal variceal bleeding is a common complication of decompensated liver cirrhosis (LC). Some studies have reported that reflux oesophagitis (RE) is a risk factor for upper gastrointestinal bleeding, and greatly impacts the quality of life. However, the frequency and mechanism of gastro-oesophageal reflux disease (GERD) in LC remain unclear. The present review explored the possible pathogenesis, and analysed the advantages and disadvantages of the interventional measures and the need for implementation of these measures. By combining the comprehensive terms associated with LC, GERD and RE, EMBASE, Medline/PubMed and the Cochrane Library were systematically searched. The underlying pathological mechanism of GERD in LC was summarized: Transient relaxation of the lower oesophageal sphincter, delayed gastric emptying, increased intra-abdominal pressure, increased intragastric pressure and excessive nitric oxide production destroyed the 'anti-reflux barrier', causing gastric content reflux. Proton pump inhibitors (PPIs) have been widely used empirically to lower the risk of oesophageal venous rupture and bleeding. However, long-term use of acid inhibitors in patients with LC may induce complications, such as spontaneous bacterial peritonitis. The metabolic half-life of PPIs is prolonged in patients with severe liver function impairment. Therefore, the indications for using acid inhibitors lack clarity. However, after endoscopic oesophageal variceal eradication, additional benefits may be gained from the long-term use of PPIs in small doses.
Collapse
Affiliation(s)
- Fei Yu
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Yue Zhu
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Na Li
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Hong-Fang Fu
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Zhi Jiang
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Xiao-Yi Zhang
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Liang Zeng
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Xiao-Yu Hu
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| |
Collapse
|
|
9
|
Shimose S, Sugimoto R, Hiraoka A, Tanaka M, Iwamoto H, Tanaka Y, Tada F, Ohama H, Niizeki T, Shirono T, Moriyama E, Noda Y, Kamachi N, Nakano M, Kuromatsu R, Koga H, Kawaguchi T. Significance of ramucirumab following atezolizumab plus bevacizumab therapy for hepatocellular carcinoma using real-world data. Hepatol Res 2023; 53:116-126. [PMID: 36316794 DOI: 10.1111/hepr.13852] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 10/20/2022] [Accepted: 10/22/2022] [Indexed: 11/04/2022]
Abstract
AIM Few studies have reported the efficacy and safety of ramucirumab (RAM) after atezolizumab plus bevacizumab (Atezo/Beva) treatment and the overall associated outcomes. Thus, we aimed to evaluate the therapeutic effects and safety of RAM post-treatment with Atezo/Beva. METHODS This retrospective study enrolled 46 patients with unresectable hepatocellular carcinoma who were treated with RAM. The patients were classified into the RAM administered following Atezo/Beva failure (n = 12) or RAM administered following other drug failure (n = 34) groups. Progression-free survival (PFS), overall survival (OS), and adverse event (AE) rates were assessed. RESULTS There were significant differences in the objective response rates and disease control rates between the RAM administered following Atezo/Beva and RAM administered following others groups (objective response rate 33.3%. vs. 0.0%, p = 0.001; disease control rate 83.3% vs. 32.3, p = 0.001). Although there was no significant difference in the OS rates, the median PFS rates in the RAM administered following Atezo/Beva group was significantly higher than in the RAM administered following others group (PFS 3.9 months. vs. 1.9 months, p = 0.047). The AE rates were comparable between the two groups; ascites was the most common AE (45.6%). Using decision tree analysis, the presence of splenomegaly and body mass index (BMI) < 19.8 were the first and second splitting variables for RAM-related ascites, respectively. CONCLUSIONS The therapeutic effect of RAM increased in patients with Atezo/Beva failure. Patients with splenomegaly and low BMI should be monitored for ascites during RAM treatment.
Collapse
Affiliation(s)
- Shigeo Shimose
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Rie Sugimoto
- Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | | | - Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Yuki Tanaka
- Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Fujimasa Tada
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Hideko Ohama
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Takashi Niizeki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Tomotake Shirono
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Etsuko Moriyama
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Yu Noda
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Naoki Kamachi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Masahito Nakano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Ryoko Kuromatsu
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| |
Collapse
|
|
10
|
Deltenre P, Zanetto A, Saltini D, Moreno C, Schepis F. The role of transjugular intrahepatic portosystemic shunt in patients with cirrhosis and ascites: Recent evolution and open questions. Hepatology 2023; 77:640-658. [PMID: 35665949 DOI: 10.1002/hep.32596] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 05/14/2022] [Accepted: 05/16/2022] [Indexed: 01/28/2023]
Abstract
In selected patients with cirrhosis and ascites, transjugular intrahepatic portosystemic shunt (TIPS) placement improves control of ascites and may reduce mortality. In this review, we summarize the current knowledge concerning the use of TIPS for the treatment of ascites in patients with cirrhosis, from pathophysiology of ascites formation to hemodynamic consequences, patient selection, and technical issues of TIPS insertion. The combination of these factors is important to guide clinical decision-making and identify the best strategy for each individual patient. There is still a need to identify the best timing for TIPS placement in the natural history of ascites (recurrent vs. refractory) as well as which type and level of renal dysfunction is acceptable when TIPS is proposed for the treatment of ascites in cirrhosis. Future studies are needed to define the optimal stent diameter according to patient characteristics and individual risk of shunt-related side effects, particularly hepatic encephalopathy and insufficient cardiac response to hemodynamic consequences of TIPS insertion.
Collapse
Affiliation(s)
- Pierre Deltenre
- Department of Gastroenterology, Hepatopancreatology, and Digestive Oncology , CUB Hôpital Erasme, Université Libre de Bruxelles , Brussels , Belgium.,Department of Gastroenterology and Hepatology , CHU UCL Namur, Université Catholique de Louvain , Yvoir , Belgium.,Department of Gastroenterology and Hepatology , Clinique St Luc , Bouge , Belgium
| | - Alberto Zanetto
- Division of Gastroenterology, Hepatic Hemodynamic Laboratory , Azienda Ospedaliero-Universitaria di Modena, and University of Modena and Reggio Emilia , Modena , Italy.,Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology , Padova University Hospital , Padova , Italy
| | - Dario Saltini
- Division of Gastroenterology, Hepatic Hemodynamic Laboratory , Azienda Ospedaliero-Universitaria di Modena, and University of Modena and Reggio Emilia , Modena , Italy
| | - Christophe Moreno
- Department of Gastroenterology, Hepatopancreatology, and Digestive Oncology , CUB Hôpital Erasme, Université Libre de Bruxelles , Brussels , Belgium.,Laboratory of Experimental Gastroenterology , Université Libre de Bruxelles , Brussels , Belgium
| | - Filippo Schepis
- Division of Gastroenterology, Hepatic Hemodynamic Laboratory , Azienda Ospedaliero-Universitaria di Modena, and University of Modena and Reggio Emilia , Modena , Italy
| |
Collapse
|
|
11
|
de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C. Reply to: 'Management of portal hypertension in patients treated with atezolizumab and bevacizumab for hepatocellular carcinoma'. J Hepatol 2022; 77:567-568. [PMID: 35526788 DOI: 10.1016/j.jhep.2022.04.029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 12/04/2022]
Affiliation(s)
| | - Jaume Bosch
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland; Instituts d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and CIBERehd, University of Barcelona, Spain
| | | | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Cristina Ripoll
- Internal Medicine IV, Universitätsklinikum Jena, Friedrich Schiller University, Jena, Germany
| |
Collapse
|
|
12
|
Rodrigues SG, Mendoza YP, Bosch J. Investigational drugs in early clinical development for portal hypertension. Expert Opin Investig Drugs 2022; 31:825-842. [PMID: 35758843 DOI: 10.1080/13543784.2022.2095259] [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: 11/04/2022]
Abstract
INTRODUCTION Advanced chronic liver disease is considered a reversible condition after removal of the primary aetiological factor. This has led to a paradigm shift in which portal hypertension (PH) is a reversible complication of cirrhosis. The pharmacologic management of PH is centered on finding targets to modify the natural history of cirrhosis and PH. AREAS COVERED This paper offers an overview of the use of pharmacological strategies in early clinical development that modify PH. Papers included were selected from searching clinical trials sites and PubMed from the last 10 years. EXPERT OPINION A paradigm shift has generated a new concept of PH in cirrhosis as a reversible complication of a potentially curable disease. Decreasing portal pressure to prevent decompensation and further complications of cirrhosis that may lead liver transplantation or death is a goal. Therapeutic strategies also aspire achieve total or partial regression of fibrosis thus eliminating the need for treatment or screening of PH.
Collapse
Affiliation(s)
- Susana G Rodrigues
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.,Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Yuly P Mendoza
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.,Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland.,Graduate School for Health Sciences (GHS), University of Bern
| | - Jaime Bosch
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.,Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| |
Collapse
|
|
13
|
González DV, López KPP, Nungaray SAV, Madrigal LGM. Tratamiento de ascitis refractaria: estrategias actuales y nuevo panorama de los beta bloqueadores no selectivos. GASTROENTEROLOGIA Y HEPATOLOGIA 2022; 45:715-723. [PMID: 35257809 DOI: 10.1016/j.gastrohep.2022.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 02/09/2022] [Accepted: 02/21/2022] [Indexed: 02/07/2023]
|
|
14
|
Zhao Z, Zhang C, Lin J, Zheng L, Li H, Qi X, Huo H, Lou X, Hammock BD, Hwang SH, Bao Y, Luo M. COX-2/sEH Dual Inhibitor PTUPB Alleviates CCl 4 -Induced Liver Fibrosis and Portal Hypertension. Front Med (Lausanne) 2022; 8:761517. [PMID: 35004731 PMCID: PMC8734593 DOI: 10.3389/fmed.2021.761517] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 12/02/2021] [Indexed: 01/02/2023] Open
Abstract
Background: 4-(5-phenyl-3-{3-[3-(4-trifluoromethylphenyl)-ureido]-propyl}-pyrazol-1-yl) -benzenesulfonamide (PTUPB), a dual cyclooxygenase-2 (COX-2)/soluble epoxide hydrolase (sEH) inhibitor, was found to alleviate renal, pulmonary fibrosis and liver injury. However, few is known about the effect of PTUPB on liver cirrhosis. In this study, we aimed to explore the role of PTUPB in liver cirrhosis and portal hypertension (PHT). Method: Rat liver cirrhosis model was established via subcutaneous injection of carbon tetrachloride (CCl4) for 16 weeks. The experimental group received oral administration of PTUPB (10 mg/kg) for 4 weeks. We subsequently analyzed portal pressure (PP), liver fibrosis, inflammation, angiogenesis, and intra- or extrahepatic vascular remodeling. Additionally, network pharmacology was used to investigate the possible mechanisms of PTUPB in live fibrosis. Results: CCl4 exposure induced liver fibrosis, inflammation, angiogenesis, vascular remodeling and PHT, and PTUPB alleviated these changes. PTUPB decreased PP from 17.50 ± 4.65 to 6.37 ± 1.40 mmHg, reduced collagen deposition and profibrotic factor. PTUPB alleviated the inflammation and bile duct proliferation, as indicated by decrease in serum interleukin-6 (IL-6), liver cytokeratin 19 (CK-19), transaminase, and macrophage infiltration. PTUPB also restored vessel wall thickness of superior mesenteric arteries (SMA) and inhibited intra- or extrahepatic angiogenesis and vascular remodeling via vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), etc. Moreover, PTUPB induced sinusoidal vasodilation by upregulating endothelial nitric oxide synthase (eNOS) and GTP-cyclohydrolase 1 (GCH1). In enrichment analysis, PTUPB engaged in multiple biological functions related to cirrhosis, including blood pressure, tissue remodeling, immunological inflammation, macrophage activation, and fibroblast proliferation. Additionally, PTUPB suppressed hepatic expression of sEH, COX-2, and transforming growth factor-β (TGF-β). Conclusion: 4-(5-phenyl-3-{3-[3-(4-trifluoromethylphenyl)-ureido]-propyl}-pyrazol-1-yl)- benzenesulfonamide ameliorated liver fibrosis and PHT by inhibiting fibrotic deposition, inflammation, angiogenesis, sinusoidal, and SMA remodeling. The molecular mechanism may be mediated via the downregulation of the sEH/COX-2/TGF-β.
Collapse
Affiliation(s)
- Zhifeng Zhao
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chihao Zhang
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiayun Lin
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Zheng
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongjie Li
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoliang Qi
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haizhong Huo
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaolou Lou
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bruce D Hammock
- Department of Entomology, Nematology and UC Davis Comprehensive Cancer Center, Davis, CA, United States
| | - Sung Hee Hwang
- Department of Entomology, Nematology and UC Davis Comprehensive Cancer Center, Davis, CA, United States
| | - Yongyang Bao
- Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Meng Luo
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
15
|
Dajti E, Renzulli M, Colecchia A, Bacchi-Reggiani ML, Milandri M, Rossini B, Ravaioli F, Marasco G, Alemanni LV, Ierardi AM, Carrafiello G, Pinzani M, Azzaroli F, Mazzella G, Golfieri R, Festi D. Size and location of spontaneous portosystemic shunts predict the risk of decompensation in cirrhotic patients. Dig Liver Dis 2022; 54:103-110. [PMID: 33414086 DOI: 10.1016/j.dld.2020.12.114] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 11/29/2020] [Accepted: 12/17/2020] [Indexed: 12/29/2022]
Abstract
BACKGROUND The prognostic role of spontaneous portosystemic shunts (SPSS) has been poorly investigated. AIMS To evaluate the impact of the presence of SPSS, as well as their characteristics, on the risk of decompensation. METHODS This is a retrospective cohort study of 235 advanced chronic liver disease (ACLD) patients with available imaging examination, transient elastography, and upper endoscopy. ACLD was defined as liver stiffness measurement (LSM) >10 kPa. Competitive risk analyses were performed to identify the factors associated with the main outcome. RESULTS SPSS were reported in 141 (60%) of the patients. Non-viral etiology was independently associated with SPSS presence [Odds-Ratio (OR): 2.743;95%-Interval-of-Confidence (IC):1.129-6.664]. During a follow-up of 37 (20-63) months, SPSS were found predictors of any decompensation type [Subhazard Ratio (SHR):2.264; 95%-IC:1.259-4.071], independently from a history of decompensation or high-risk-varices presence. The risk of complications was higher in patients with large (SHR: 3.775; 95%-IC: 2.016-7.070) and multiple (SHR:3.832; 95%-IC: 2.004-7.330) shunts, and in those with gastrorenal shunts (SHR:2.636; 95%-IC:1.521-4.569). CONCLUSIONS The presence, size, and number of SPSS predict not only the risk of hepatic encephalopathy but that of any type of decompensation across all stages of cirrhosis. Future studies should explore the possibility of treating shunts to prevent decompensation.
Collapse
Affiliation(s)
- Elton Dajti
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, Bologna 40138, Italy
| | - Matteo Renzulli
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Via Massarenti 9, Bologna 40138, Italy
| | - Antonio Colecchia
- Unit of Gastroenterology, Borgo Trento University Hospital of Verona, P.le Aristide Stefani 1, Verona 37126, Italy.
| | - Maria Letizia Bacchi-Reggiani
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Via Massarenti 9, Bologna 40138, Italy
| | - Matteo Milandri
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Via Massarenti 9, Bologna 40138, Italy
| | - Benedetta Rossini
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, Bologna 40138, Italy
| | - Federico Ravaioli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, Bologna 40138, Italy
| | - Giovanni Marasco
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, Bologna 40138, Italy
| | - Luigina Vanessa Alemanni
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, Bologna 40138, Italy
| | - Anna Maria Ierardi
- Diagnostic and Interventional Radiology, San Paolo Hospital, Milan, Italy
| | | | - Massimo Pinzani
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and UCL, London, United Kingdom
| | - Francesco Azzaroli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, Bologna 40138, Italy
| | - Giuseppe Mazzella
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, Bologna 40138, Italy
| | - Rita Golfieri
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Via Massarenti 9, Bologna 40138, Italy
| | - Davide Festi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, Bologna 40138, Italy
| |
Collapse
|
|
16
|
Cognitive Impairement in Non-Cirrhotic Portal Hypertension: Highlights on Physiopathology, Diagnosis and Management. J Clin Med 2021; 11:jcm11010101. [PMID: 35011842 PMCID: PMC8745274 DOI: 10.3390/jcm11010101] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 12/19/2021] [Accepted: 12/21/2021] [Indexed: 11/18/2022] Open
Abstract
Hepatic encephalopathy (HE) is one of the most frequent complications of cirrhosis. Several studies and case reports have shown that cognitive impairment may also be a tangible complication of portal hypertension secondary to chronic portal vein thrombosis and to porto-sinusoidal vascular disease (PSVD). In these conditions, representing the main causes of non-cirrhotic portal hypertension (NCPH) in the Western world, both overt and minimal/covert HE occurs in a non-neglectable proportion of patients, even lower than in cirrhosis, and it is mainly sustained by the presence of large porto-systemic shunt. In these patients, the liver function is usually preserved or only mildly altered, and the development of porto-systemic shunt is either spontaneous or iatrogenically frequent; HE is an example of type-B HE. To date, in the absence of strong evidence and large cooperative studies, for the diagnosis and the management of HE in NCPH, the same approach used for HE occurring in cirrhosis is applied. The aim of this paper is to provide an overview of type B hepatic encephalopathy, focusing on its pathophysiology, diagnostic tools and management in patients affected by porto-sinusoidal vascular disease and chronic portal vein thrombosis.
Collapse
|
|
17
|
Rajesh S, Philips CA, Ahamed R, Abduljaleel JK, Nair DC, Augustine P. Friend or Foe? Spontaneous Portosystemic Shunts in Cirrhosis-Current Understanding and Future Prospects. Can J Gastroenterol Hepatol 2021; 2021:8795115. [PMID: 34422711 PMCID: PMC8376437 DOI: 10.1155/2021/8795115] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 08/02/2021] [Indexed: 02/07/2023] Open
Abstract
Portal hypertension (PHT) in cirrhosis results from increased resistance to splanchnic blood flow secondary to parenchymal and vascular changes within the liver. In an attempt to counteract the increased portal pressure, two mechanisms simultaneously occur: splanchnic vasodilatation and formation of spontaneous portosystemic shunts (SPSS). Long considered to be a compensatory mechanism to decompress the portal venous system, it is now well established that SPSS are not only inefficient in decreasing the portal pressure but also contribute to reduced hepatocyte perfusion and increased splanchnic blood flow and resistance, associated with worsening PHT. Recent studies have described a high prevalence of SPSS in cirrhosis patients, increasing with liver dysfunction, and observed an association between the presence of SPSS and worse clinical outcomes. In cirrhosis patients with preserved liver functions, the presence of SPSS independently increases the risk of hepatic encephalopathy, variceal bleeding, and ascites, and reduces transplant-free survival. Moreover, the presence of SPSS in patients undergoing transjugular intrahepatic portosystemic shunting and liver transplant has been shown to variably affect the postprocedural outcome. This article provides an overview of the current understanding of the role of SPSS in the natural history of liver cirrhosis and their status as a therapeutic target and an imaging biomarker to identify patients at higher risk of developing complications of PHT.
Collapse
Affiliation(s)
- Sasidharan Rajesh
- Department of GI and HPB Interventional Radiology, The Liver Institute, Center of Excellence in GI Sciences, Rajagiri Hospital, Aluva, Kerala, India
| | - Cyriac Abby Philips
- Department of Clinical and Translational Hepatology, The Liver Institute, Center of Excellence in GI Sciences, Rajagiri Hospital, Aluva, Kerala, India
| | - Rizwan Ahamed
- Department Gastroenterology and Advanced GI Endoscopy, Center of Excellence in GI Sciences, Rajagiri Hospital, Aluva, Kerala, India
| | - Jinsha K Abduljaleel
- Department Gastroenterology and Advanced GI Endoscopy, Center of Excellence in GI Sciences, Rajagiri Hospital, Aluva, Kerala, India
| | - Dinu Chandran Nair
- Department of GI and HPB Interventional Radiology, The Liver Institute, Center of Excellence in GI Sciences, Rajagiri Hospital, Aluva, Kerala, India
| | - Philip Augustine
- Department Gastroenterology and Advanced GI Endoscopy, Center of Excellence in GI Sciences, Rajagiri Hospital, Aluva, Kerala, India
| |
Collapse
|
|
18
|
Allaire M, Rudler M, Thabut D. Portal hypertension and hepatocellular carcinoma: Des liaisons dangereuses…. Liver Int 2021; 41:1734-1743. [PMID: 34051060 DOI: 10.1111/liv.14977] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/17/2021] [Accepted: 05/24/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Portal hypertension (PHT) and hepatocellular carcinoma (HCC) are major complication of cirrhosis which significantly contribute to morbidity and mortality. In this review, we aim to describe the consequences of both angiogenesis and inflammation in the pathogenesis of PHT and HCC, but also the difficulty to propose adapted treatment when PHT and HCC coexist in the same patients. METHODS Studies for review in this article were retrieved from the PubMed database using literature published in English until March 2021. RESULTS Portal hypertension occurs secondary to an increase of intrahepatic vascular resistances, the opening of portosystemic collateral vessels and the formation of neovessels, related to vascular endothelial growth factor (VEGF). Recently, bacterial translocation-mediated inflammation was also identified as a major contributor to PHT. Interestingly, VEGF and chronic inflammation also contribute to HCC occurrence. As PHT and HCC often coexist in the same patient, management of PHT and its related complications as well as HCC treatment appear more complex. Indeed, PHT-related complications such as significant ascites may hamper the access to HCC treatment and the presence of HCC is also independently associated with poor prognosis in patients with acute variceal bleeding related to PHT. Due to their respective mechanism of action, the combination of Atezolizumab and Bevacizumab for advanced HCC may impact the level of PHT and its related complications and to date, no real-life data are available. CONSLUSIONS Appropriate evaluation and treatment of PHT remains a major issue in order to improve the outcome of HCC patients.
Collapse
Affiliation(s)
- Manon Allaire
- Service d'Hépatolo-gastroentérologie, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, AP-HP, Sorbonne Université, Paris, France.,Inserm U1149, Centre de Recherche sur l'Inflammation, France Faculté de Médecine Xavier Bichat, Université Paris Diderot, Paris, France
| | - Marika Rudler
- Service d'Hépatolo-gastroentérologie, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, AP-HP, Sorbonne Université, Paris, France.,INSERM, Centre de Recherche Saint-Antoine (CRSA), Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Paris, France
| | - Dominique Thabut
- Service d'Hépatolo-gastroentérologie, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, AP-HP, Sorbonne Université, Paris, France.,INSERM, Centre de Recherche Saint-Antoine (CRSA), Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Paris, France
| |
Collapse
|
|
19
|
Fofiu R, Bende F, Popescu A, Șirli R, Miuţescu B, Sporea I. Assessing Baveno VI Criteria Using Liver Stiffness Measured with a 2D-Shear Wave Elastography Technique. Diagnostics (Basel) 2021; 11:737. [PMID: 33919033 PMCID: PMC8142982 DOI: 10.3390/diagnostics11050737] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/12/2021] [Accepted: 04/20/2021] [Indexed: 12/18/2022] Open
Abstract
The present study evaluates the performance of Baveno VI criteria, using liver stiffness (LS) assessed with a 2D-SWE elastography technique, for predicting high-risk varices (HRV) in patients with compensated advanced chronic liver disease (cACLD). A secondary aim was to determine whether the use of spleen stiffness measurements (SSMs), as additional criteria, increases the performance of the 2D-SWE Baveno VI criteria. Data were collected from 208 subjects with cACLD, who underwent abdominal ultrasound, liver and spleen stiffness measurements, and upper digestive endoscopy. HRV were defined as grade 1 esophageal varices (EV) with red wale marks, grade 2/3 EV, and gastric varices. A total of 35.6% (74/208) of the included subjects had HRV. The optimal LS cut-off value for predicting HRV was 12 kPa (AUROC-0.80). Using both LS cut-off value < 12 kPa and a platelet cut-off value > 150 × 109 cells/L as criteria to exclude HRV, 52/208 (25%) subjects were selected, 88.5% (46/52) were without EV, 9.6% (5/52) had grade 1 EV, and 1.9% (1/52) had HRV. Thus 98% of the subjects were correctly classified as having or not having HRV and 25% of the surveillance endoscopies could have been avoided. Using SS < 13.2 kPa and a platelet cut-off value > 150 × 109 cells/L as additional criteria for the patients that were outside the initial ones, 32.7% of the surveillance endoscopies could have been avoided.
Collapse
Affiliation(s)
| | - Felix Bende
- Department of Gastroenterology and Hepatology, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania; (R.F.); (A.P.); (R.Ș.); (B.M.); (I.S.)
| | | | | | | | | |
Collapse
|
|
20
|
Li H. Angiogenesis in the progression from liver fibrosis to cirrhosis and hepatocelluar carcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:217-233. [PMID: 33131349 DOI: 10.1080/17474124.2021.1842732] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: Persistent inflammation and hypoxia are strong stimulus for pathological angiogenesis and vascular remodeling, and are also the most important elements resulting in liver fibrosis. Sustained inflammatory process stimulates fibrosis to the end-point of cirrhosis and sinusoidal portal hypertension is an important feature of cirrhosis. Neovascularization plays a pivotal role in collateral circulation formation of portal vein, mesenteric congestion, and high perfusion. Imbalance of hepatic artery and portal vein blood flow leads to the increase of hepatic artery inflow, which is beneficial to the formation of nodules. Angiogenesis contributes to progression from liver fibrosis to cirrhosis and hepatocellular carcinoma (HCC) and anti-angiogenesis therapy can improve liver fibrosis, reduce portal pressure, and prolong overall survival of patients with HCC. Areas covers: This paper will try to address the difference of the morphological characteristics and mechanisms of neovascularization in the process from liver fibrosis to cirrhosis and HCC and further compare the different efficacy of anti-angiogenesis therapy in these three stages. Expert opinion: More in-depth understanding of the role of angiogenesis factors and the relationship between angiogenesis and other aspects of the pathogenesis and transformation may be the key to enabling future progress in the treatment of patients with liver fibrosis, cirrhosis, and HCC.
Collapse
Affiliation(s)
- Hui Li
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine , Chengdu, Sichuan Province, P. R. China
| |
Collapse
|
|
21
|
Novel therapeutics for portal hypertension and fibrosis in chronic liver disease. Pharmacol Ther 2020; 215:107626. [DOI: 10.1016/j.pharmthera.2020.107626] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 06/30/2020] [Indexed: 02/06/2023]
|
|
22
|
Hassan M, Moghadamrad S, Sorribas M, Muntet SG, Kellmann P, Trentesaux C, Fraudeau M, Nanni P, Wolski W, Keller I, Hapfelmeier S, Shroyer NF, Wiest R, Romagnolo B, De Gottardi A. Paneth cells promote angiogenesis and regulate portal hypertension in response to microbial signals. J Hepatol 2020; 73:628-639. [PMID: 32205193 DOI: 10.1016/j.jhep.2020.03.019] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 02/27/2020] [Accepted: 03/13/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Paneth cells (PCs) synthesize and secrete antimicrobial peptides that are key mediators of host-microbe interactions, establishing a balance between intestinal microflora and enteric pathogens. We observed that their number increases in experimental portal hypertension and aimed to investigate the mechanisms by which these cells can contribute to the regulation of portal pressure. METHODS We first treated Math1Lox/LoxVilcreERT2 mice with tamoxifen to induce the complete depletion of intestinal PCs. Subsequently, we performed partial portal vein or bile duct ligation. We then studied the effects of these interventions on hemodynamic parameters, proliferation of blood vessels and the expression of genes regulating angiogenesis. Intestinal organoids were cultured and exposed to different microbial products to study the composition of their secreted products (by proteomics) and their effects on the proliferation and tube formation of endothelial cells (ECs). In vivo confocal laser endomicroscopy was used to confirm the findings on blood vessel proliferation. RESULTS Portal hypertension was significantly attenuated in PC-depleted mice compared to control mice and was associated with a decrease in portosystemic shunts. Depletion of PCs also resulted in a significantly decreased density of blood vessels in the intestinal wall and mesentery. Furthermore, we observed reduced expression of intestinal genes regulating angiogenesis in Paneth cell depleted mice using arrays and next generation sequencing. Tube formation and wound healing responses were significantly decreased in ECs treated with conditioned media from PC-depleted intestinal organoids exposed to intestinal microbiota-derived products. Proteomic analysis of conditioned media in the presence of PCs revealed an increase in factors regulating angiogenesis and additional metabolic processes. In vivo endomicroscopy showed decreased vascular proliferation in the absence of PCs. CONCLUSIONS These results suggest that in response to intestinal flora and microbiota-derived factors, PCs secrete not only antimicrobial peptides, but also pro-angiogenic signaling molecules, thereby promoting intestinal and mesenteric angiogenesis and regulating portal hypertension. LAY SUMMARY Paneth cells are present in the lining of the small intestine. They prevent the passage of bacteria from the intestine into the blood circulation by secreting substances to fight bacteria. In this paper, we discovered that these substances not only act against bacteria, but also increase the quantity of blood vessels in the intestine and blood pressure in the portal vein. This is important, because high blood pressure in the portal vein may result in several complications which could be targeted with novel approaches.
Collapse
Affiliation(s)
- Mohsin Hassan
- Department for Biomedical Research, Hepatology, University of Bern, Switzerland
| | - Sheida Moghadamrad
- Department for Biomedical Research, Hepatology, University of Bern, Switzerland; Inselspital, Hepatology, University of Bern, Switzerland (Clinic of Visceral Surgery and Medicine, Inselspital, Berne, Switzerland)
| | - Marcel Sorribas
- Department for Biomedical Research, Gastroenterology, University of Bern, Switzerland
| | - Sergi G Muntet
- Department for Biomedical Research, Hepatology, University of Bern, Switzerland
| | - Philipp Kellmann
- Department for Biomedical Research, Hepatology, University of Bern, Switzerland
| | - Coralie Trentesaux
- INSERM, U106, Institut Cochin, F-75014 Paris, France; CNRS, UMR8104, F-75014 Paris, France; Université paris Descartes Sorbonne paris Cité, Paris, France
| | - Marie Fraudeau
- INSERM, U106, Institut Cochin, F-75014 Paris, France; CNRS, UMR8104, F-75014 Paris, France; Université paris Descartes Sorbonne paris Cité, Paris, France
| | - Paolo Nanni
- Functional Genomic Centre, Swiss Federal Institute of Technology, Zurich, Switzerland
| | - Witold Wolski
- Functional Genomic Centre, Swiss Federal Institute of Technology, Zurich, Switzerland
| | - Irene Keller
- Department for Biomedical Research and Swiss Institute of Bioinformatics, University of Bern, Switzerland
| | | | - Noah F Shroyer
- Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
| | - Reiner Wiest
- Department for Biomedical Research, Gastroenterology, University of Bern, Switzerland; Inselspital, Hepatology, University of Bern, Switzerland (Clinic of Visceral Surgery and Medicine, Inselspital, Berne, Switzerland)
| | - Beatrice Romagnolo
- INSERM, U106, Institut Cochin, F-75014 Paris, France; CNRS, UMR8104, F-75014 Paris, France; Université paris Descartes Sorbonne paris Cité, Paris, France
| | - Andrea De Gottardi
- Department for Biomedical Research, Hepatology, University of Bern, Switzerland; Inselspital, Hepatology, University of Bern, Switzerland (Clinic of Visceral Surgery and Medicine, Inselspital, Berne, Switzerland); Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, Università della Svizzera Italiana, Lugano, Switzerland.
| |
Collapse
|
|
23
|
Fortea JI, Puerto M, Fernández-Mena C, Asensio I, Arriba M, Almagro J, Bañares J, Ripoll C, Bañares R, Vaquero J. Sevoflurane versus ketamine+diazepam anesthesia for assessing systemic and hepatic hemodynamics in rats with non-cirrhotic portal hypertension. PLoS One 2020; 15:e0233778. [PMID: 32469999 PMCID: PMC7259621 DOI: 10.1371/journal.pone.0233778] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Accepted: 05/12/2020] [Indexed: 11/30/2022] Open
Abstract
The selection of the anesthetic regime is a crucial component in many experimental animal studies. In rodent models of liver disease, the combination of ketamine and diazepam (KD), generally by the intramuscular (i.m.) route, has traditionally been the anesthesia of choice for the evaluation of systemic and hepatic hemodynamics but it presents several problems. Here, we compared the performance of inhalational sevoflurane (Sevo) against the KD combination as the anesthesia used for hemodynamic studies involving the measurement of portal pressure in normal rats (Ctrl) and rats with non-cirrhotic portal hypertension induced by partial portal vein ligation (PPVL). Compared with Ctrl rats, rats with PPVL presented characteristic alterations that were not influenced by the anesthetic regime, which included liver atrophy, splenomegaly, increased plasma fibrinogen, decreased alkaline phosphatase and glycemia, and frequent ascites. The use of the KD combination presented several disadvantages compared with the inhalational anesthesia with sevoflurane, including considerable mortality, a higher need of dose adjustments to maintain an optimal depth of anesthesia, increases of heart rate, and alteration of blood biochemical parameters such as the concentration of aspartate aminotransferase, lactate, and lactic dehydrogenase. Rats anesthetized with sevoflurane, on the other hand, presented lower respiratory rates. Importantly, the anesthetic regime did not influence the measurement of portal pressure either in Ctrl or PPVL rats, with the increase of portal pressure being similar in Sevo- and KD- anesthetized groups of PPVL rats compared with their respective control groups. Overall, our results suggest that anesthesia with sevoflurane is preferable to the combination of KD for performing systemic and hepatic hemodynamic studies in rats with non-cirrhotic portal hypertension.
Collapse
Affiliation(s)
- José Ignacio Fortea
- HepatoGastro Lab, Servicio de Ap. Digestivo del HGU Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Servicio de Digestivo, Hospital Universitario Marqués de Valdecilla, Santander, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Marta Puerto
- HepatoGastro Lab, Servicio de Ap. Digestivo del HGU Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Carolina Fernández-Mena
- HepatoGastro Lab, Servicio de Ap. Digestivo del HGU Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Iris Asensio
- HepatoGastro Lab, Servicio de Ap. Digestivo del HGU Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - María Arriba
- Servicio de Bioquímica Clínica del HGU Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Jorge Almagro
- HepatoGastro Lab, Servicio de Ap. Digestivo del HGU Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Juan Bañares
- HepatoGastro Lab, Servicio de Ap. Digestivo del HGU Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Cristina Ripoll
- HepatoGastro Lab, Servicio de Ap. Digestivo del HGU Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Innere Medizin I, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany
| | - Rafael Bañares
- HepatoGastro Lab, Servicio de Ap. Digestivo del HGU Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Facultad de Medicina, Universidad Complutense, Madrid, Spain
| | - Javier Vaquero
- HepatoGastro Lab, Servicio de Ap. Digestivo del HGU Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- * E-mail:
| |
Collapse
|
|
24
|
Rodriguez EA, Perez R, Zhang N, Lim ES, Miller C, Schwartz MA, McGirr AJ, Srinivasan A, Hewitt W, Silva AC, Rakela J, Vargas HE. Clinical Outcomes of Portosystemic Shunts on the Outcome of Liver Transplantation. Liver Transpl 2020; 26:693-701. [PMID: 31872966 DOI: 10.1002/lt.25710] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 12/07/2019] [Indexed: 12/24/2022]
Abstract
Spontaneous portosystemic shunts (SPSSs) have been associated with worse clinical outcomes in the pre-liver transplantation (LT) setting, but little is known about their post-LT impacts. Our aim was to compare LT candidates with and without SPSSs and assess the impact of SPSSs on patient mortality and graft survival in the post-LT setting. Patients 18 years or older with abdominal imaging done prior to LT were included. Exclusion criteria were the presence of pre-LT surgical shunts, LT indications other than cirrhosis, and combined solid organ transplantations. SPSSs were classified as absent, small, or large according to their maximum diameter (8 mm). Multiple variables that could influence the post-LT course were extracted for analysis. Patient and graft survival were estimated using the Kaplan-Meier method and were compared between groups using a log-rank test. The project received institutional review board approval. We extracted data from 326 patients. After comparing patients without SPSS or with small or large SPSSs, no statistical difference was found for overall patient survival: no SPSS (n = 8/63), reference; small SPSS (n = 18/150), hazard ratio (HR), 1.05 (95% confidence interval [CI], 0.45-2.46); and large SPSS (n = 6/113), HR, 0.60 (95% CI, 0.20-1.78); P = 0.20. Also, no difference was found for graft survival: no SPSS (n = 11/63), reference; small SPSS (n = 21/150), HR, 0.80 (95% CI, 0.38-1.70); large SPSS (n = 11/113), HR, 0.59 (95% CI, 0.25-1.40); P = 0.48. Similarly, no statistical significance was found for these variables when comparing if the graft used was procured from a donation after circulatory death donor versus a donation after brain death donor. In conclusion, the previously described association between SPSSs and worse clinical outcomes in pre-LT patients seems not to persist once patients undergo LT. This study suggests that no steps to correct SPSS intraoperatively are necessary.
Collapse
Affiliation(s)
- Eduardo A Rodriguez
- Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Phoenix, AZ.,Division of Transplantation Center, Mayo Clinic Arizona, Phoenix, AZ
| | - Rachel Perez
- Mayo Clinic Alix School of Medicine, Mayo Clinic Arizona, Phoenix, AZ
| | - Nan Zhang
- Department of Health Science Research, Section of Biostatistics, Mayo Clinic Arizona, Phoenix, AZ
| | - Elisabeth S Lim
- Department of Health Science Research, Section of Biostatistics, Mayo Clinic Arizona, Phoenix, AZ
| | | | | | - Aidan J McGirr
- Department of Radiology, Mayo Clinic Arizona, Phoenix, AZ
| | - Ananth Srinivasan
- Division of Transplantation Center, Mayo Clinic Arizona, Phoenix, AZ.,Division of Transplantation Surgery, Mayo Clinic Arizona, Phoenix, AZ
| | - Winston Hewitt
- Division of Transplantation Center, Mayo Clinic Arizona, Phoenix, AZ.,Division of Transplantation Surgery, Mayo Clinic Arizona, Phoenix, AZ
| | - Alvin C Silva
- Department of Radiology, Mayo Clinic Arizona, Phoenix, AZ
| | - Jorge Rakela
- Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Phoenix, AZ.,Division of Transplantation Center, Mayo Clinic Arizona, Phoenix, AZ
| | - Hugo E Vargas
- Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Phoenix, AZ.,Division of Transplantation Center, Mayo Clinic Arizona, Phoenix, AZ
| |
Collapse
|
|
25
|
Ramirez-Pedraza M, Fernández M. Interplay Between Macrophages and Angiogenesis: A Double-Edged Sword in Liver Disease. Front Immunol 2019; 10:2882. [PMID: 31921146 PMCID: PMC6927291 DOI: 10.3389/fimmu.2019.02882] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 11/25/2019] [Indexed: 12/19/2022] Open
Abstract
During chronic liver disease, macrophages support angiogenesis, not only by secreting proangiogenic growth factors and matrix-remodeling proteases, but also by physically interacting with the sprouting vasculature to assist the formation of complex vascular networks. In the liver, macrophages acquire specific characteristics becoming Kupffer cells and working to ensure protection and immunotolerance. Angiogenesis is another double-edged sword in health and disease and it is the biggest ally of macrophages allowing its dissemination. Angiogenesis and fibrosis may occur in parallel in several tissues as macrophages co-localize with newly formed vessels and secrete cytokines, interleukins, and growth factors that will activate other cell types in the liver such as hepatic stellate cells and liver sinusoidal endothelial cells, promoting extracellular matrix accumulation and fibrogenesis. Vascular endothelial growth factor, placental growth factor, and platelet-derived growth factor are the leading secreted factors driving pathological angiogenesis and consequently increasing macrophage infiltration. Tumor development in the liver has been widely linked to macrophage-mediated chronic inflammation in which epidermal growth factors, STAT3 and NF-kβ are some of the most relevant signaling molecules involved. In this article, we review the link between macrophages and angiogenesis at molecular and cellular levels in chronic liver disease.
Collapse
Affiliation(s)
- Marta Ramirez-Pedraza
- Angiogenesis in Liver Disease Research Group, IDIBAPS Biomedical Research Institute, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Mercedes Fernández
- Angiogenesis in Liver Disease Research Group, IDIBAPS Biomedical Research Institute, Hospital Clinic, University of Barcelona, Barcelona, Spain.,Biomedical Research Networking Center on Hepatic and Digestive Disease (CIBEREHD), Institute of Health Carlos III, Madrid, Spain
| |
Collapse
|
|
26
|
Abstract
This review chapter describes the current knowledge about the nature of pericytes in the gut, their interaction with endothelial cells in blood vessels, and their pathophysiological functions in the setting of chronic liver disease. In particular, it focuses on the role of these vascular cell types and related molecular signaling pathways in pathological angiogenesis associated with liver disease and in the establishment of the gut-vascular barrier and the potential implications in liver disease through the gut-liver axis.
Collapse
|
|
27
|
Gelman S, Salteniene V, Pranculis A, Skieceviciene J, Zykus R, Petrauskas D, Kupcinskas L, Canbay A, Link A, Kupcinskas J. Plasma Nogo-A and placental growth factor levels are associated with portal hypertension in patients with liver cirrhosis. World J Gastroenterol 2019; 25:2935-2946. [PMID: 31249451 PMCID: PMC6589742 DOI: 10.3748/wjg.v25.i23.2935] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 04/18/2019] [Accepted: 04/29/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Clinically significant portal hypertension (CSPH) and severe portal hypertension (SPH) increase the risk for decompensation and life-threatening complications in liver cirrhosis. Pathologic angiogenesis might contribute to the formation of these conditions. Placental growth factor (PlGF) and Nogo-A protein are biomarkers of pathological angiogenesis, but data on their role in liver cirrhosis and portal hypertension is scarce. AIM To determine plasma levels of PlGF and Nogo-A in patients with liver cirrhosis, CSPH, SPH and potential to predict portal hypertension. METHODS A cohort of 122 patients with hepatitis C virus and/or alcohol-induced liver cirrhosis with characterized hepatic venous pressure gradient (HVPG) were included in the study. Demographic data, medical history, Child-Turcotte-Pugh and Model of End Stage liver disease score, clinical chemistry, liver stiffness values were recorded on the day of the procedure prior HVPG measurement. The degree of portal hypertension was determined by the invasive HVPG measurement. Nogo-A and PlGF plasma levels were evaluated using enzyme linked immunosorbent assay. The control group consisted of 30 healthy age- and sex- matched individuals. RESULTS Peripheral PlGF levels were higher and Nogo-A levels were lower in patients with liver cirrhosis (23.20 vs 9.85; P < 0.0001 and 2.19 vs 3.12; P = 0.004 respectively). There was a positive linear correlation between peripheral levels of PlGF and HVPG (r = 0.338, P = 0.001) and negative linear correlation between the peripheral Nogo-A levels and HVPG (r = -0.267, P = 0.007). PlGF levels were higher in CSPH and SPH (P = 0.006; P < 0.0001) whereas Nogo-A levels were lower (P = 0.01; P < 0.033). Area under the curve for the diagnosis of CSPH for PlGF was 0.68 (P = 0.003) and for Nogo-A - 0.67 (P = 0.01); for SPH 0.714 (P < 0.0001) and 0.65 (P = 0.014) respectively. PlGF levels were higher and Nogo-A levels were lower in patients with esophageal varices (P < 0.05). PlGF cut-off value of 25 pg/mL distinguished patients with CSPH at 55.7% sensitivity and 76.7% specificity; whereas Nogo-A cut-off value of 1.12 ng/mL was highly specific (93.1%) for the diagnosis of CSPH. CONCLUSION Plasma PlGF levels were higher while Nogo-A levels were lower in patients with liver cirrhosis and portal hypertension. Biomarkers showed moderate predictive value in determining CSPH and SPH.
Collapse
Affiliation(s)
- Sigita Gelman
- Department of Gastroenterology, Medical Academy, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Violeta Salteniene
- Institute for Digestive Research, Medical Academy, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Andrius Pranculis
- Department of Radiology, Medical Academy, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Jurgita Skieceviciene
- Institute for Digestive Research, Medical Academy, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Romanas Zykus
- Department of Gastroenterology, Medical Academy, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Dalius Petrauskas
- Department of Gastroenterology, Medical Academy, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Limas Kupcinskas
- Institute for Digestive Research and Department of Gastroenterology, Medical Academy, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Ali Canbay
- Department of Gastroenterology, Hepatology and Infectious Diseases Otto-von-Guericke University, Magdeburg 39106, Germany
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases Otto-von-Guericke University, Magdeburg 39106, Germany
| | - Juozas Kupcinskas
- Institute for Digestive Research and Department of Gastroenterology, Medical Academy, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| |
Collapse
|
|
28
|
Deng Z, Zhang S, Ge S, Kong F, Cao S, Pan Z. Gexia-Zhuyu Decoction Attenuates Carbon Tetrachloride-Induced Liver Fibrosis in Mice Partly via Liver Angiogenesis Mediated by Myeloid Cells. Med Sci Monit 2019; 25:2835-2844. [PMID: 30995213 PMCID: PMC6482864 DOI: 10.12659/msm.913481] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Background This study aims to demonstrate the underlying correlation between the resolution of liver fibrosis induced by Gexia-Zhuyu decoction (GZD) treatment and myeloid cell-mediated angiogenesis. Material/Methods A liver fibrosis mouse model induced by carbon tetrachloride (CCl4) intervention was employed in this study. Dynamics of blood liver function parameters were followed. The liver pathology was detected by Sirius Red and Masson staining. Matrix metalloproteinase (MMP) 2/9, tissue inhibitors of metalloproteinase (TIMP)-1/2, and vascular endothelial growth factor (VEGF)-A expression levels were measured. Bone marrow chimera mice were generated by transfer of bone morrow cells from green fluorescent protein (GFP)-knockin mice into irradiated wild-type mice, and were used it to visualize the role of myeloid cells on the fibrosis resolution induced by GZD treatment. Results The result of Sirius Red and Masson staining and the dynamics of blood liver function parameters showed that 5 weeks of GZD treatment attenuated the severity of liver fibrosis with continual CCl4 administration. GZD treatment promoted the expression of MMP2/9 and repressed the heightened level of TIMP-1/2 in the recovery phase. More notably, the increased VEGF-A and augmented endothelial progenitor cells were observed in the liver and blood in mice that received GZD, and contributed to the remodeling of hepatic vascular though the CXCL12/CXCR4 axis. Then, chimera mice with GFP-positive bone marrow cells were used to show angiogenesis driven by GZD-induced myeloid cell motivation. We found that GZD facilitated myeloid cells binding to the vascular CXCR4 and induced the resolution of fibrosis. Conclusions This study shows that activation of myeloid cells induced by GZD administration accelerates the functional angiogenesis, which benefits the resolution of CCl4-induced liver fibrosis.
Collapse
Affiliation(s)
- Zhengming Deng
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland)
| | - Shihu Zhang
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland)
| | - Shaohua Ge
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland)
| | - Fanping Kong
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland)
| | - Shibing Cao
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland)
| | - Zhaoxia Pan
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland)
| |
Collapse
|
|
29
|
Shenoda B, Boselli J. Vascular syndromes in liver cirrhosis. Clin J Gastroenterol 2019; 12:387-397. [PMID: 30980261 DOI: 10.1007/s12328-019-00956-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Accepted: 02/20/2019] [Indexed: 02/08/2023]
Abstract
Liver cirrhosis is associated with multiple vascular syndromes affecting almost all body systems. Many of these syndromes are directly related to impaired liver function and sometimes reversible after liver transplantation while others arise secondary to portal hypertension and ascites. Altered expression of angiogenic and vasoactive compounds (most importantly nitric oxide), endothelial dysfunction, dysregulated neurohormonal control, and systemic inflammatory state play differential roles in mediating homeostatic instability and abnormal vasogenic response. Important vascular features encountered in liver disease include portal hypertension, splanchnic overflow, abnormal angiogenesis and shunts, portopulmonary syndrome, hepatopulmonary syndrome, and systemic hyperdynamic circulation. Redistribution of effective circulatory volume deviating from vital organs and pooling in splanchnic circulation is also encountered in liver patients which may lead to devastating outcomes as hepatorenal syndrome. Etiologically, vascular syndromes are not isolated phenomena and vascular dysfunction in one system may lead to the development of another in a different system. This review focuses on understanding the pathophysiological factors underlying vascular syndromes related to chronic liver disease and the potential links among them. Many of these syndromes are associated with high mortality, thus it is crucial to look for early biomarkers for these syndromes and develop novel preventive and therapeutic strategies.
Collapse
Affiliation(s)
- Botros Shenoda
- Department of Medicine, Drexel University College of Medicine, Philadelphia, PA, 19102, USA
| | - Joseph Boselli
- Department of Medicine, Drexel University College of Medicine, Philadelphia, PA, 19102, USA. .,Drexel Internal Medicine, 205 N. Broad Street, Philadelphia, 19107, USA.
| |
Collapse
|
|
30
|
Scheiner B, Ulbrich G, Mandorfer M, Reiberger T, Müller C, Waneck F, Trauner M, Kölblinger C, Ferlitsch A, Sieghart W, Peck-Radosavljevic M, Pinter M. Short- and long-term effects of transarterial chemoembolization on portal hypertension in patients with hepatocellular carcinoma. United European Gastroenterol J 2019; 7:850-858. [PMID: 31316789 PMCID: PMC6620878 DOI: 10.1177/2050640619840199] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 02/12/2019] [Indexed: 12/20/2022] Open
Abstract
Background Transarterial chemoembolization (TACE) affects hepatic perfusion, and might
have an impact on portal pressure in patients with hepatocellular carcinoma
(HCC). Objective The objective of this article is to report the secondary outcome “hepatic
hemodynamics” from the AVATACE trial, a prospective randomized,
placebo-controlled trial on the efficacy of conventional TACE in combination
with bevacizumab or placebo. Methods Hepatic venous pressure gradient (HVPG) was measured at baseline (prior to
first TACE), within nine days (“acute effects”), two months (“intermediate
effects”) and six months (“long-term effects”) after the first TACE. Results Of 28 patients with early-intermediate stage HCC, n = 20
(71%) had clinically significant portal hypertension (CSPH, HVPG ≥ 10 mmHg)
at baseline (median, 12 (interquartile range (IQR): 9–19) mmHg). TACE had
neither “acute effects” nor “intermediate effects” on HVPG. However, in 13
patients with available HVPG measurement at month 6, there was a significant
increase in HVPG (median, 16 (IQR: 11–19) mmHg) compared with baseline
(median, 10 (IQR: 5–12) mmHg; p = 0.007). Portal
hypertension-related complications occurred exclusively in patients with
CSPH (8 (40%) vs 0). Conclusions Repeated TACE was associated with a significant long-term increase in HVPG.
This should be considered when deciding whether to continue with TACE or
switch to systemic treatment, since CSPH drives the development of
complications.
Collapse
Affiliation(s)
- Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria.,Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria
| | - Gregor Ulbrich
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria
| | - Christian Müller
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Fredrik Waneck
- Division of Cardiovascular and Interventional Radiology, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Claus Kölblinger
- Division of Cardiovascular and Interventional Radiology, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria.,Department of Radiology, Krankenhaus Barmherzige Schwestern Ried, Ried, Austria
| | - Arnulf Ferlitsch
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Department of Internal Medicine, Krankenhaus Barmherzige Brüder Wien, Vienna Austria
| | - Wolfgang Sieghart
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Markus Peck-Radosavljevic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Department of Internal Medicine and Gastroenterology, Hepatology, Endocrinology, Rheumatology and Nephrology including Centralized Emergency Department, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| |
Collapse
|
|
31
|
Portal hypertension: The desperate search for the placenta. Curr Res Transl Med 2018; 67:56-61. [PMID: 30503816 DOI: 10.1016/j.retram.2018.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 09/17/2018] [Accepted: 09/30/2018] [Indexed: 12/10/2022]
Abstract
We propose that the circulatory impairments produced, in both portal hypertension and liver cirrhosis, to a certain degree resemble those characterizing prenatal life in the fetus. In fact, the left-right circulatory syndrome is common in cirrhotic patients and in the fetus. Thus, in patients with portal hypertension and chronic liver failure, the re-expression of a blood circulation comparable to fetal circulation is associated with the development of similar amniotic functions, i.e., ascites production and placenta functions, and portal vascular enteropathy. Therefore, these re-expressed embryonic functions are extra-embryonic and responsible for prenatal trophism and development.
Collapse
|
|
32
|
Vilaseca M, Guixé-Muntet S, Fernández-Iglesias A, Gracia-Sancho J. Advances in therapeutic options for portal hypertension. Therap Adv Gastroenterol 2018; 11:1756284818811294. [PMID: 30505350 PMCID: PMC6256317 DOI: 10.1177/1756284818811294] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 10/15/2018] [Indexed: 02/04/2023] Open
Abstract
Portal hypertension represents one of the major clinical consequences of chronic liver disease, having a deep impact on patients' prognosis and survival. Its pathophysiology defines a pathological increase in the intrahepatic vascular resistance as the primary factor in its development, being subsequently aggravated by a paradoxical increase in portal blood inflow. Although extensive preclinical and clinical research in the field has been developed in recent decades, no effective treatment targeting its primary mechanism has been defined. The present review critically summarizes the current knowledge in portal hypertension therapeutics, focusing on those strategies driven by the disease pathophysiology and underlying cellular mechanisms.
Collapse
Affiliation(s)
- Marina Vilaseca
- Hepatic Hemodynamic Laboratory, IDIBAPS
Biomedical Research Institute, Barcelona, Spain
| | - Sergi Guixé-Muntet
- Department of Biomedical Research, University of
Bern, Bern, Switzerland
| | | | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, Barcelona
Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute,
CIBEREHD, Rosselló 149, 4th floor, 08036 Barcelona, Spain
| |
Collapse
|
|
33
|
Hsieh YH, Huang HC, Chang CC, Chuang CL, Lee FY, Hsu SJ, Huang YH, Hou MC, Lee SD. Nucleos(t)ide Analogs Do Not Independently Influence Hepatic Fibrosis and Portal Hypertension beyond Viral Suppression in CBDL-Induced Cirrhotic Rat. J Pharmacol Exp Ther 2018; 367:260-266. [PMID: 30194095 DOI: 10.1124/jpet.118.250431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Accepted: 08/07/2018] [Indexed: 11/22/2022] Open
Abstract
Chronic hepatitis is the major cause of liver cirrhosis and portal hypertension. Several factors affect portal pressure, including liver fibrosis, splanchnic vasodilatation, and pathologic angiogenesis. Nucleos(t)ide analogs (NUCs), the oral antiviral agents, effectively attenuate chronic hepatitis B-related liver cirrhosis and portal hypertension via viral suppression and alleviation of hepatitis. On the other hand, NUCs affect tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), and nitric oxide, which participate in fibrogenesis, vasodilatation, and angiogenesis. However, whether NUCs independently influence liver fibrosis and portal hypertension beyond viral suppression is unknown. This study thus aimed to evaluate the influences of three frequently used NUCs in rats with nonviral cirrhosis. Male Sprague-Dawley rats received common bile duct ligation (CBDL) to induce cholestatic cirrhosis and portal hypertension. The rats were randomly allocated into four groups, treated by mouth with lamivudine (30 mg/kg per day), entecavir (0.09 mg/kg per day), tenofovir (50 mg/kg per day), or distilled water (vehicle control) from the 15th day after CBDL. On the 29th day, liver cirrhosis- and portal hypertension-related parameters were evaluated. The results showed that chronic NUCs treatment did not affect hemodynamic parameters, plasma TNF-α concentration, and hepatic fibrogenesis protein expressions in rats with nonviral cirrhosis. Though the mesenteric VEGF receptor 2 phosphorylation was downregulated in NUCs-treated groups, the splanchnic angiogenesis was not influenced. In conclusion, lamivudine, entecavir, and tenofovir had no additional effects on liver cirrhosis and portal hypertension in rats with nonviral cirrhosis.
Collapse
Affiliation(s)
- Yu-Hsin Hsieh
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.-H.Hs, H.-C.H., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H.) and Division of General Medicine, Department of Medicine, (Y.-H.Hs, H.-C.H., C.-C.C., C.-L.C.), Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (H.-C.H., C.-C.C., C.-L.C., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H., S.-D.L.); and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan (S.-D.L.)
| | - Hui-Chun Huang
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.-H.Hs, H.-C.H., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H.) and Division of General Medicine, Department of Medicine, (Y.-H.Hs, H.-C.H., C.-C.C., C.-L.C.), Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (H.-C.H., C.-C.C., C.-L.C., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H., S.-D.L.); and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan (S.-D.L.)
| | - Ching-Chih Chang
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.-H.Hs, H.-C.H., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H.) and Division of General Medicine, Department of Medicine, (Y.-H.Hs, H.-C.H., C.-C.C., C.-L.C.), Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (H.-C.H., C.-C.C., C.-L.C., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H., S.-D.L.); and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan (S.-D.L.)
| | - Chiao-Lin Chuang
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.-H.Hs, H.-C.H., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H.) and Division of General Medicine, Department of Medicine, (Y.-H.Hs, H.-C.H., C.-C.C., C.-L.C.), Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (H.-C.H., C.-C.C., C.-L.C., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H., S.-D.L.); and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan (S.-D.L.)
| | - Fa-Yauh Lee
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.-H.Hs, H.-C.H., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H.) and Division of General Medicine, Department of Medicine, (Y.-H.Hs, H.-C.H., C.-C.C., C.-L.C.), Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (H.-C.H., C.-C.C., C.-L.C., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H., S.-D.L.); and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan (S.-D.L.)
| | - Shao-Jung Hsu
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.-H.Hs, H.-C.H., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H.) and Division of General Medicine, Department of Medicine, (Y.-H.Hs, H.-C.H., C.-C.C., C.-L.C.), Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (H.-C.H., C.-C.C., C.-L.C., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H., S.-D.L.); and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan (S.-D.L.)
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.-H.Hs, H.-C.H., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H.) and Division of General Medicine, Department of Medicine, (Y.-H.Hs, H.-C.H., C.-C.C., C.-L.C.), Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (H.-C.H., C.-C.C., C.-L.C., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H., S.-D.L.); and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan (S.-D.L.)
| | - Ming-Chih Hou
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.-H.Hs, H.-C.H., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H.) and Division of General Medicine, Department of Medicine, (Y.-H.Hs, H.-C.H., C.-C.C., C.-L.C.), Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (H.-C.H., C.-C.C., C.-L.C., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H., S.-D.L.); and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan (S.-D.L.)
| | - Shou-Dong Lee
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.-H.Hs, H.-C.H., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H.) and Division of General Medicine, Department of Medicine, (Y.-H.Hs, H.-C.H., C.-C.C., C.-L.C.), Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan (H.-C.H., C.-C.C., C.-L.C., F.-Y.L., S.-J.H., Y.-H.Hu, M.-C.H., S.-D.L.); and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan (S.-D.L.)
| |
Collapse
|
|
34
|
Garbuzenko DV, Arefyev NO, Kazachkov EL. Antiangiogenic therapy for portal hypertension in liver cirrhosis: Current progress and perspectives. World J Gastroenterol 2018; 24:3738-3748. [PMID: 30197479 PMCID: PMC6127663 DOI: 10.3748/wjg.v24.i33.3738] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Revised: 07/09/2018] [Accepted: 07/16/2018] [Indexed: 02/06/2023] Open
Abstract
Developing medicines for hemodynamic disorders that are characteristic of cirrhosis of the liver is a relevant problem in modern hepatology. The increase in hepatic vascular resistance to portal blood flow and subsequent hyperdynamic circulation underlie portal hypertension (PH) and promote its progression, despite the formation of portosystemic collaterals. Angiogenesis and vascular bed restructurization play an important role in PH pathogenesis as well. In this regard, strategic directions in the therapy for PH in cirrhosis include selectively decreasing hepatic vascular resistance while preserving or increasing portal blood flow, and correcting hyperdynamic circulation and pathological angiogenesis. The aim of this review is to describe the mechanisms of angiogenesis in PH and the methods of antiangiogenic therapy. The PubMed database, the Google Scholar retrieval system, and the reference lists from related articles were used to search for relevant publications. Articles corresponding to the aim of the review were selected for 2000-2017 using the keywords: "liver cirrhosis", "portal hypertension", "pathogenesis", "angiogenesis", and "antiangiogenic therapy". Antiangiogenic therapy for PH was the inclusion criterion. In this review, we have described angiogenesis inhibitors and their mechanism of action in relation to PH. Although most of them were studied only in animal experiments, this selective therapy for abnormally growing newly formed vessels is pathogenetically reasonable to treat PH and associated complications.
Collapse
Affiliation(s)
| | - Nikolay Olegovich Arefyev
- Department of Pathological Anatomy and Forensic Medicine, South Ural State Medical University, Chelyabinsk 454092, Russia
| | - Evgeniy Leonidovich Kazachkov
- Department of Pathological Anatomy and Forensic Medicine, South Ural State Medical University, Chelyabinsk 454092, Russia
| |
Collapse
|
|
35
|
Faillaci F, Marzi L, Critelli R, Milosa F, Schepis F, Turola E, Andreani S, Vandelli G, Bernabucci V, Lei B, D'Ambrosio F, Bristot L, Cavalletto L, Chemello L, Sighinolfi P, Manni P, Maiorana A, Caporali C, Bianchini M, Marsico M, Turco L, de Maria N, Del Buono M, Todesca P, di Lena L, Romagnoli D, Magistri P, di Benedetto F, Bruno S, Taliani G, Giannelli G, Martinez‐Chantar M, Villa E. Liver Angiopoietin-2 Is a Key Predictor of De Novo or Recurrent Hepatocellular Cancer After Hepatitis C Virus Direct-Acting Antivirals. Hepatology 2018; 68:1010-1024. [PMID: 29604220 PMCID: PMC6175123 DOI: 10.1002/hep.29911] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 02/19/2018] [Accepted: 03/25/2018] [Indexed: 12/14/2022]
Abstract
Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC). In study 1, we studied the proangiogenic liver microenvironment in 242 DAA-treated chronic hepatitis C patients with advanced fibrosis. Angiopoietin-2 (ANGPT2) expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent, de novo, nonrecurrent HCC, or patients never developing HCC. Circulating ANGPT2,vascular endothelial growth factor (VEGF), and C-reactive protein (CRP) were also measured. In study 2, we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical, clinical, hemodynamic, endoscopic, elastographic, and echo-Doppler work-up was performed in both studies. In study 1, no patients without cirrhosis developed HCC. Of 183 patients with cirrhosis, 14 of 28 (50.0%) with previous HCC recurred whereas 21 of 155 (13.5%) developed de novo HCC. Patients with recurrent and de novo HCCs had significantly higher liver fibrosis (LF) scores, portal pressure, and systemic inflammation than nonrecurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients, tumor and nontumor ANGPT2 showed an inverse relationship with portal vein velocity (PVv; r = -0.412, P = 0.037 and r = -0.409, P = 0.047 respectively) and a positive relationship with liver stiffness (r = 0.526, P = 0.007; r = 0.525, P = 0.003 respectively). Baseline circulating VEGF and cirrhotic liver ANGPT2 were significantly related (r = 0.414, P = 0.044). VEGF increased during DAAs, remaining stably elevated at 3-month follow-up, when it significantly related with serum ANGPT2 (r = 0.531, P = 0.005). ANGPT2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with risk of HCC recurrence (odds ratio [OR], 1.137; 95% confidence interval [CI], 1.044-1.137; P = 0.003) or occurrence (OR, 1.604; 95% CI, 1.080-2.382; P = 0.019). In study 2, DAA treatment (OR, 4.770; 95% CI, 1.395-16.316; P = 0.013) and large varices (OR, 3.857; 95% CI, 1.127-13.203; P = 0.032) were independent predictors of de novo HCC. CONCLUSION Our study indicates that DAA-mediated increase of VEGF favors HCC recurrence/occurrence in susceptible patients, that is, those with more severe fibrosis and splanchnic collateralization, who already have abnormal activation in liver tissues of neo-angiogenetic pathways, as shown by increased ANGPT2. (Hepatology 2018; 00:000-000).
Collapse
Affiliation(s)
- Francesca Faillaci
- Gastroenterology Unit, Department of Internal MedicineUniversity of Modena and Reggio EmiliaModenaItaly
- WomenInHepatology Network
| | - Luca Marzi
- Gastroenterology Unit, Department of Internal MedicineUniversity of Modena and Reggio EmiliaModenaItaly
| | - Rosina Critelli
- Gastroenterology Unit, Department of Internal MedicineUniversity of Modena and Reggio EmiliaModenaItaly
- WomenInHepatology Network
| | - Fabiola Milosa
- National Institute of Gastroenterology, “S. de Bellis” Research HospitalCastellana GrotteBariItaly
- WomenInHepatology Network
| | - Filippo Schepis
- Gastroenterology Unit, Department of Internal MedicineUniversity of Modena and Reggio EmiliaModenaItaly
| | - Elena Turola
- National Institute of Gastroenterology, “S. de Bellis” Research HospitalCastellana GrotteBariItaly
- WomenInHepatology Network
| | - Silvia Andreani
- Gastroenterology Unit, Department of Internal MedicineUniversity of Modena and Reggio EmiliaModenaItaly
| | - Gabriele Vandelli
- Gastroenterology Unit, Department of Internal MedicineUniversity of Modena and Reggio EmiliaModenaItaly
| | - Veronica Bernabucci
- Gastroenterology Unit, Department of Internal MedicineUniversity of Modena and Reggio EmiliaModenaItaly
- WomenInHepatology Network
| | - Barbara Lei
- Gastroenterology Unit, Department of Internal MedicineUniversity of Modena and Reggio EmiliaModenaItaly
- WomenInHepatology Network
| | - Federica D'Ambrosio
- Gastroenterology Unit, Department of Internal MedicineUniversity of Modena and Reggio EmiliaModenaItaly
- WomenInHepatology Network
| | - Laura Bristot
- Gastroenterology Unit, Department of Internal MedicineUniversity of Modena and Reggio EmiliaModenaItaly
- WomenInHepatology Network
| | - Luisa Cavalletto
- Department of MedicineUniversity of PaduaPaduaItaly
- WomenInHepatology Network
| | - Liliana Chemello
- Department of MedicineUniversity of PaduaPaduaItaly
- WomenInHepatology Network
| | - Pamela Sighinolfi
- Department of PathologyUniversity of Modena and Reggio EmiliaModenaItaly
| | - Paola Manni
- Department of PathologyUniversity of Modena and Reggio EmiliaModenaItaly
| | - Antonino Maiorana
- Department of PathologyUniversity of Modena and Reggio EmiliaModenaItaly
| | - Cristian Caporali
- Department of RadiologyUniversity of Modena and Reggio EmiliaModenaItaly
| | - Marcello Bianchini
- Gastroenterology Unit, Department of Internal MedicineUniversity of Modena and Reggio EmiliaModenaItaly
| | - Maria Marsico
- Gastroenterology Unit, Department of Internal MedicineUniversity of Modena and Reggio EmiliaModenaItaly
- WomenInHepatology Network
| | - Laura Turco
- Gastroenterology Unit, Department of Internal MedicineUniversity of Modena and Reggio EmiliaModenaItaly
- WomenInHepatology Network
| | - Nicola de Maria
- Gastroenterology Unit, Department of Internal MedicineUniversity of Modena and Reggio EmiliaModenaItaly
| | - Mariagrazia Del Buono
- Gastroenterology Unit, Department of Internal MedicineUniversity of Modena and Reggio EmiliaModenaItaly
- WomenInHepatology Network
| | - Paola Todesca
- Gastroenterology Unit, Department of Internal MedicineUniversity of Modena and Reggio EmiliaModenaItaly
- WomenInHepatology Network
| | - Luca di Lena
- National Institute of Gastroenterology, “S. de Bellis” Research HospitalCastellana GrotteBariItaly
| | - Dante Romagnoli
- Gastroenterology Unit, Department of Internal MedicineUniversity of Modena and Reggio EmiliaModenaItaly
| | - Paolo Magistri
- Liver and Multivisceral Transplant CenterUniversity of Modena and Reggio EmiliaModenaItaly
| | - Fabrizio di Benedetto
- Liver and Multivisceral Transplant CenterUniversity of Modena and Reggio EmiliaModenaItaly
| | - Savino Bruno
- Humanitas University and Humanitas Research Hospital RozzanoMilanItaly
| | - Gloria Taliani
- Department of Clinical MedicineUniversity of Rome ‘La Sapienza’RomeItaly
- WomenInHepatology Network
| | - Gianluigi Giannelli
- National Institute of Gastroenterology, “S. de Bellis” Research HospitalCastellana GrotteBariItaly
| | - Maria‐Luz Martinez‐Chantar
- CIC bioGUNE, Centro de Investigación Cooperativa en Biociencias. Technology Park of Bizkaia, Bizkaia, Spain. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)Instituto de Salud Carlos IIIMadridSpain
- WomenInHepatology Network
| | - Erica Villa
- Gastroenterology Unit, Department of Internal MedicineUniversity of Modena and Reggio EmiliaModenaItaly
- WomenInHepatology Network
| |
Collapse
|
|
36
|
Königshofer P, Brusilovskaya K, Schwabl P, Reiberger T. Animal models of portal hypertension. Biochim Biophys Acta Mol Basis Dis 2018; 1865:1019-1030. [PMID: 30055295 DOI: 10.1016/j.bbadis.2018.07.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Revised: 07/14/2018] [Accepted: 07/16/2018] [Indexed: 12/12/2022]
Abstract
Chronic liver diseases ultimately lead to cirrhosis and portal hypertension (PHT). Indeed, PHT is a major cause of severe complications, while medical treatment is limited to non-selective beta blockers. Sophisticated animal models are needed to investigate novel treatment options for different etiologies of liver disease, effective anti-fibrotic agents as well as vasoactive drugs against PHT. In this review, we present some of the most common animal models of liver disease and PHT - including pre-hepatic, intra-hepatic and post-hepatic PHT in rodents. Methodology for induction, considerations for disease etiology, advantages and limitations and practical issues of these animal models are discussed. The appropriate and sensible use of animal models in preclinical research supporting the 3R concept of replacement, reduction and refinement is highlighted.
Collapse
Affiliation(s)
- P Königshofer
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - K Brusilovskaya
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - P Schwabl
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - T Reiberger
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
|
37
|
Therapeutic siRNA targeting endothelial KDR decreases portosystemic collateralization in portal hypertension. Sci Rep 2017; 7:14791. [PMID: 29093528 PMCID: PMC5665956 DOI: 10.1038/s41598-017-14818-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 10/13/2017] [Indexed: 02/08/2023] Open
Abstract
Development of portosystemic collateral vessels and gastroesophageal varices is responsible for the most serious clinical consequences of portal hypertension, but effective clinical therapies are limited. Here we developed and investigated the therapeutic potential of an innovative liposomally-formulated short-interfering RNA (siRNA) technology based on clinical stage components, capable to attenuate production of the endothelial kinase insert domain receptor (KDR), which controls portosystemic collateralization and contributes to disease progression and aggravation. These siRNAs were first validated in vitro, and then, their therapeutic potential on portosystemic collateralization and pathological angiogenesis was tested in vivo in mouse models of portal hypertension (portal vein-ligation). siRNAKDR-lipoplexes efficiently transported siRNAKDR to vascular endothelial cells in mesenteric microvenules and portal vein of portal hypertensive mice, where collaterogenesis and angiogenesis take place. This systemic treatment significantly downregulated pathological KDR overexpression, without causing complete KDR knockout, preserving homeostatic baseline KDR levels and thus limiting adverse effects. siRNAKDR-lipoplex-induced endothelial-specific KDR knockdown drastically reduced by 73% the portosystemic collateralization, and impaired the pathologic angiogenic potential of vascular endothelial cells at different levels (cell proliferation, sprouting and remodeling). Targeting endothelial KDR with therapeutic siRNAKDR-lipoplexes could be a promising and plausible treatment modality for attenuating the formation of portosystemic collaterals in a clinical setting.
Collapse
|
|
38
|
Aller MA, Arias N, Peral I, García-Higarza S, Arias JL, Arias J. Embrionary way to create a fatty liver in portal hypertension. World J Gastrointest Pathophysiol 2017; 8:39-50. [PMID: 28573066 PMCID: PMC5437501 DOI: 10.4291/wjgp.v8.i2.39] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 01/18/2017] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
Portal hypertension in the rat by triple partial portal vein ligation produces an array of splanchnic and systemic disorders, including hepatic steatosis. In the current review these alterations are considered components of a systemic inflammatory response that would develop through three overlapping phenotypes: The neurogenic, the immune and the endocrine. These three inflammatory phenotypes could resemble the functions expressed during embryonic development of mammals. In turn, the inflammatory phenotypes would be represented in the embryo by two functional axes, that is, a coelomic-amniotic axis and a trophoblastic yolk-sac or vitelline axis. In this sense, the inflammatory response developed after triple partial portal vein ligation in the rat would integrate both functional embryonic axes on the liver interstitial space of Disse. If so, this fact would favor the successive development of steatosis, steatohepatitis and fibrosis. Firstly, these recapitulated embryonic functions would produce the evolution of liver steatosis. In this way, this fat liver could represent a yolk-sac-like in portal hypertensive rats. After that, the systemic recapitulation of these embryonic functions in experimental prehepatic portal hypertension would consequently induce a gastrulation-like response in which a hepatic wound healing reaction or fibrosis occur. In conclusion, studying the mechanisms involved in embryonic development could provide key results for a better understanding of the nonalcoholic fatty liver disease etiopathogeny.
Collapse
|
|
39
|
Schwabl P, Laleman W. Novel treatment options for portal hypertension. Gastroenterol Rep (Oxf) 2017; 5:90-103. [PMID: 28533907 PMCID: PMC5421460 DOI: 10.1093/gastro/gox011] [Citation(s) in RCA: 23] [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: 03/12/2017] [Accepted: 03/12/2017] [Indexed: 12/13/2022] Open
Abstract
Portal hypertension is most frequently associated with cirrhosis and is a major driver for associated complications, such as variceal bleeding, ascites or hepatic encephalopathy. As such, clinically significant portal hypertension forms the prelude to decompensation and impacts significantly on the prognosis of patients with liver cirrhosis. At present, non-selective β-blockers, vasopressin analogues and somatostatin analogues are the mainstay of treatment but these strategies are far from satisfactory and only target splanchnic hyperemia. In contrast, safe and reliable strategies to reduce the increased intrahepatic resistance in cirrhotic patients still represent a pending issue. In recent years, several preclinical and clinical trials have focused on this latter component and other therapeutic avenues. In this review, we highlight novel data in this context and address potentially interesting therapeutic options for the future.
Collapse
Affiliation(s)
- Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Wim Laleman
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| |
Collapse
|
|
40
|
Ma R, Chen J, Liang Y, Lin S, Zhu L, Liang X, Cai X. Sorafenib: A potential therapeutic drug for hepatic fibrosis and its outcomes. Biomed Pharmacother 2017; 88:459-468. [PMID: 28122312 DOI: 10.1016/j.biopha.2017.01.107] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Revised: 01/17/2017] [Accepted: 01/17/2017] [Indexed: 12/16/2022] Open
|
|
41
|
Wang L, Zhao X, Feng Y, Ma X, Wu H, Zhu Q. Intrahepatic angiogenesis increases portal hypertension in hepatitis B patients with cirrhosis. Hepatol Res 2017; 47:E94-E103. [PMID: 27115574 DOI: 10.1111/hepr.12732] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 04/19/2016] [Accepted: 04/22/2016] [Indexed: 01/17/2023]
Abstract
AIM It remains unclear whether intrahepatic angiogenesis increases portal hypertension (PH) in hepatitis B with cirrhosis. We aim to investigate the relationship between intrahepatic angiogenesis and PH in hepatitis B patients with cirrhosis. METHODS Sixty hepatitis B patients with cirrhosis and 40 healthy subjects were included in this study. Angiogenesis markers vascular endothelial growth factor receptor-2 (VEGFR2), von Willebrand factor (vWF), and fibrosis marker α-smooth muscle actin (α-SMA) were observed by immunohistochemistry. Sirius Red staining was also used to determine liver fibrosis. Correlations between levels of intrahepatic angiogenesis and Child-Pugh classes, liver fibrosis degree, and portal vein pressure were examined. We also analyzed the relationship between levels of intrahepatic angiogenesis and complications of PH, including esophageal varices (EV), ascites, and hypersplenism. RESULTS Correlation was observed between the levels of VEGFR2 (r = 0.590, P < 0.01), vWF (r = 0.524, P < 0.01) in tissue, and Child-Pugh classes. Significant correlations were observed between levels of VEGFR2 and α-SMA (r = 0.710, P < 0.01), VEGFR2 and Sirius Red (r = 0.841, P < 0.01), vWF and α-SMA (r = 0.768, P < 0.01), and vWF and Sirius Red (r = 0.825, P < 0.01). Patients with hepatic venous pressure gradient (HVPG) ≥12 mmHg showed higher levels of VEGFR2 and vWF expression compared to those with (HVPG) <12 mmHg (2.60 ± 1.28% vs. 1.09 ± 0.73%; 5.85 ± 2.45% vs. 2.31 ± 1.34%, P < 0.01), respectively. Moreover, complications of PH, including size of esophageal varices (P < 0.01), presence of ascites (P < 0.01), and spleen volume (P < 0.01) were significantly affected by the levels of intrahepatic angiogenesis. CONCLUSION Intrahepatic angiogenesis increases PH in hepatitis B patients with cirrhosis. The study provides the potential ways to intervene in the progresses for therapeutic benefits in cirrhosis and PH.
Collapse
Affiliation(s)
- Le Wang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Xinya Zhao
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Yuemin Feng
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Xiaowen Ma
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Hao Wu
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Qiang Zhu
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| |
Collapse
|
|
42
|
Abstract
In patients with advanced liver disease with portal hypertension, portal-systemic collaterals contribute to circulatory disturbance, gastrointestinal hemorrhage, hepatic encephalopathy, ascites, hepatopulmonary syndrome and portopulmonary hypertension. Angiogenesis has a pivotal role in the formation of portal-systemic shunts. Recent research has defined many of the mediators and mechanisms involved in this angiogenic process, linking the central roles of hepatic stellate cells and endothelial cells. Studies of animal models have demonstrated the potential therapeutic impact of drugs to inhibit angiogenesis in cirrhosis. For example, inhibition of VEGF reduces portal pressure, hyperdynamic splanchnic circulation, portosystemic collateralization and liver fibrosis. An improved understanding of the role of other angiogenic factors provides hope for a novel targeted therapy for portal hypertension with a tolerable adverse effect profile.
Collapse
Affiliation(s)
- Juan Cristóbal Gana
- Department of Pediatric Gastroenterology & Nutrition, Division of Pediatrics, Escuela de Medicina, Pontificia Universidad Católica de Chile. Chile
| | - Carolina A Serrano
- Department of Pediatric Gastroenterology & Nutrition, Division of Pediatrics, Escuela de Medicina, Pontificia Universidad Católica de Chile. Chile
| | - Simon C Ling
- Division of Gastroenterology, Hepatology & Nutrition, Department of Paediatrics, University of Toronto, and The Hospital for Sick Children, Toronto, Canada
| |
Collapse
|
|
43
|
Garbuzenko DV, Arefyev NO, Belov DV. Restructuring of the vascular bed in response to hemodynamic disturbances in portal hypertension. World J Hepatol 2016; 8:1602-1609. [PMID: 28083082 PMCID: PMC5192551 DOI: 10.4254/wjh.v8.i36.1602] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 09/23/2016] [Accepted: 11/01/2016] [Indexed: 02/06/2023] Open
Abstract
In recent years, defined progress has been made in understanding the mechanisms of hemodynamic disturbances occurring in liver cirrhosis, which are based on portal hypertension. In addition to pathophysiological disorders related to endothelial dysfunction, it was revealed: There is the restructuring of the vasculature, which includes vascular remodeling and angiogenesis. In spite of the fact that these changes are the compensatory-adaptive response to the deteriorating conditions of blood circulation, taken together, they contribute to the development and progression of portal hypertension causing severe complications such as bleeding from esophageal varices. Disruption of systemic and organ hemodynamics and the formation of portosystemic collaterals in portal hypertension commence with neovascularization and splanchnic vasodilation due to the hypoxia of the small intestine mucosa. In this regard, the goal of comprehensive treatment may be to influence on the chemokines, proinflammatory cytokines, and angiogenic factors (vascular endothelial growth factor, placental growth factor, platelet-derived growth factor and others) that lead to the development of these disorders. This review is to describe the mechanisms of restructuring of the vascular bed in response to hemodynamic disturbances in portal hypertension. Development of pathogenetic methods, which allow correcting portal hypertension, will improve the efficiency of conservative therapy aimed at prevention and treatment of its inherent complications.
Collapse
Affiliation(s)
- Dmitry Victorovich Garbuzenko
- Dmitry Victorovich Garbuzenko, Nikolay Olegovich Arefyev, Department of Faculty Surgery, South Ural State Medical University, 454092 Chelyabinsk, Russia
| | - Nikolay Olegovich Arefyev
- Dmitry Victorovich Garbuzenko, Nikolay Olegovich Arefyev, Department of Faculty Surgery, South Ural State Medical University, 454092 Chelyabinsk, Russia
| | - Dmitry Vladimirovich Belov
- Dmitry Victorovich Garbuzenko, Nikolay Olegovich Arefyev, Department of Faculty Surgery, South Ural State Medical University, 454092 Chelyabinsk, Russia
| |
Collapse
|
|
44
|
Feng RB. Relationship between chronic liver disease and liver hypoxia. Shijie Huaren Xiaohua Zazhi 2016; 24:2184-2190. [DOI: 10.11569/wcjd.v24.i14.2184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The liver is an organ that metabolizes various substances very vigorously. During hepatic metabolism a large amount of oxygen needs to be provided for the liver, so the liver is vulnerable to hypoxia. Many chronic liver diseases are accompanied by liver cell hypoxia. In turn, liver cell hypoxia not only worsens liver tissue damage on the basis of primary liver lesion and inhibits hepatocellular regeneration but also accelerates liver fibrosis, cirrhosis, and even primary liver carcinoma. With chronic liver diseases exacerbating, liver hypoxia becomes more and more serious, and vice versa. This is an important mechanism by which chronic liver diseases gradually get worse and worse. As the most important hypoxia signal transduction factor in vivo, hypoxia inducible factor-1α (HIF-1α) plays an indispensable key role in the process of adaptive responses of the liver to hypoxia stimulus. Some progress in therapy for chronic liver diseases has been being made as the relationship between chronic liver diseases and liver hypoxia has been revealed and understood more deeply, especially by regulating and controlling HIF-1α and its downstream target to treat liver fibrosis. In addition, it has been found that some medicines have positive therapeutic effects on patients with chronic liver diseases through improving liver microcirculation and ameliorating liver hypoxia. However, the very complicated mechanism of interaction between chronic liver diseases and liver hypoxia, which involves a number of complex signal pathways, has not been completely elucidated, and therefore more basic and clinical studies need to be carried out for the clarification of their interaction.
Collapse
|
|
45
|
Granger DN, Holm L, Kvietys P. The Gastrointestinal Circulation: Physiology and Pathophysiology. Compr Physiol 2016; 5:1541-83. [PMID: 26140727 DOI: 10.1002/cphy.c150007] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The gastrointestinal (GI) circulation receives a large fraction of cardiac output and this increases following ingestion of a meal. While blood flow regulation is not the intense phenomenon noted in other vascular beds, the combined responses of blood flow, and capillary oxygen exchange help ensure a level of tissue oxygenation that is commensurate with organ metabolism and function. This is evidenced in the vascular responses of the stomach to increased acid production and in intestine during periods of enhanced nutrient absorption. Complimenting the metabolic vasoregulation is a strong myogenic response that contributes to basal vascular tone and to the responses elicited by changes in intravascular pressure. The GI circulation also contributes to a mucosal defense mechanism that protects against excessive damage to the epithelial lining following ingestion of toxins and/or noxious agents. Profound reductions in GI blood flow are evidenced in certain physiological (strenuous exercise) and pathological (hemorrhage) conditions, while some disease states (e.g., chronic portal hypertension) are associated with a hyperdynamic circulation. The sacrificial nature of GI blood flow is essential for ensuring adequate perfusion of vital organs during periods of whole body stress. The restoration of blood flow (reperfusion) to GI organs following ischemia elicits an exaggerated tissue injury response that reflects the potential of this organ system to generate reactive oxygen species and to mount an inflammatory response. Human and animal studies of inflammatory bowel disease have also revealed a contribution of the vasculature to the initiation and perpetuation of the tissue inflammation and associated injury response.
Collapse
Affiliation(s)
- D Neil Granger
- Department of Molecular and Cellular Physiology, LSU Health Science Center-Shreveport, Shreveport, Louisiana, USA
| | - Lena Holm
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Peter Kvietys
- Department of Physiological Sciences, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| |
Collapse
|
|
46
|
Chen Y, Wang W, Wang H, Li Y, Shi M, Li H, Yan J. Rapamycin Attenuates Splenomegaly in both Intrahepatic and Prehepatic Portal Hypertensive Rats by Blocking mTOR Signaling Pathway. PLoS One 2016; 11:e0141159. [PMID: 26734934 PMCID: PMC4703391 DOI: 10.1371/journal.pone.0141159] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 10/03/2015] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Spleen enlargement is often detected in patients with liver cirrhosis, but the precise pathogenetic mechanisms behind the phenomenon have not been clearly elucidated. We investigated the pathogenetic mechanisms of splenomegaly in both portal hypertensive patients and rats, and tried to identify the possible therapy for this disease. METHODS Spleen samples were collected from portal hypertensive patients after splenectomy. Rat models of portal hypertension were induced by common bile duct ligation and partial portal vein ligation. Spleen samples from patients and rats were used to study the characteristics of splenomegaly by histological, immunohistochemical, and western blot analyses. Rapamycin or vehicle was administered to rats to determine the contribution of mTOR signaling pathway in the development of splenomegaly. RESULTS We found that not only spleen congestion, but also increasing angiogenesis, fibrogenesis, inflammation and proliferation of splenic lymphoid tissue contributed to the development of splenomegaly in portal hypertensive patients and rats. Intriguingly, splenomegaly developed time-dependently in portal hypertensive rat that accompanied with progressive activation of mTOR signaling pathway. mTOR blockade by rapamycin profoundly ameliorated splenomegaly by limiting lymphocytes proliferation, angiogenesis, fibrogenesis and inflammation as well as decreasing portal pressure. CONCLUSIONS This study provides compelling evidence indicating that mTOR signaling activation pathway plays a key role in the pathogenesis of splenomegaly in both portal hypertensive patients and rats. Therapeutic intervention targeting mTOR could be a promising strategy for patients with portal hypertension and splenomegaly.
Collapse
Affiliation(s)
- Yunyang Chen
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Weijie Wang
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Huakai Wang
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yongjian Li
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Minmin Shi
- Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hongwei Li
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jiqi Yan
- Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- * E-mail:
| |
Collapse
|
|
47
|
Licks F, Hartmann RM, Marques C, Schemitt E, Colares JR, Soares MDC, Reys J, Fisher C, da Silva J, Marroni NP. N-acetylcysteine modulates angiogenesis and vasodilation in stomach such as DNA damage in blood of portal hypertensive rats. World J Gastroenterol 2015; 21:12351-12360. [PMID: 26604642 PMCID: PMC4649118 DOI: 10.3748/wjg.v21.i43.12351] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Revised: 05/14/2015] [Accepted: 07/18/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the antioxidant effect of N-acetylcysteine (NAC) on the stomach of rats with portal hypertension.
METHODS: Twenty-four male Wistar rats weighing ± 250 g were divided into four experimental groups (n = 6 each): Sham-operated (SO), SO + NAC, partial portal vein ligation (PPVL), and PPVL + NAC. Treatment with NAC in a dose of 10 mg/kg (i.p.) diluted in 0.6 mL of saline solution was administered daily for 7 d starting 8 d after the surgery. Animals from the PPVL and SO group received saline solution (0.6 mL) for the same period of time as the PPVL + NAC and SO + NAC group. On the 15th day the animals were anesthetized and we evaluated portal pressure by cannulating mesenteric artery. After, we removed the stomach for further analysis. We performed immunohistochemical analysis for endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), and nitrotirosine (NTT) proteins in stomach. We also evaluated eNOS and VEGF by Western blot analysis and assessed DNA damage in blood samples by the comet assay.
RESULTS: The portal hypertension group exhibited increases in portal pressure when compared to SO group (29.8 ± 1.8 vs 12.0 ± 0.3 mmHg) (P < 0.001). The same was observed when we compared the eNOS (56.8 ± 3.7 vs 13.46 ± 2.8 pixels) (P < 0.001), VEGF (34.9 ± 4.7 vs 17.46 ± 2.6 pixels) (P < 0.05), and NTT (39.01 ± 4.0 vs 12.77 ± 2.3 pixels) (P < 0.05) expression by immunohistochemistry of the PPVL animals with the SO group. The expression of eNOS (0.39 ± 0.03 vs 0.25 ± 0.03 a.μ) (P < 0.01) and VEGF (0.38 ± 0.04 vs 0.26 ± 0.04 a.μ) (P < 0.01) were also evaluated by Western blot analysis, and we observed an increase of both proteins on PPVL animals. We also evaluated the DNA damage by comet assay, and observed an increase on damage index and damage frequency on those animals. NAC decreased portal pressure values in PPVL + NAC animals (16.46 ± 2 vs 29.8 ± 1.8 mmHg) (P < 0.001) when compared to PPVL. The expression of eNOS (14.60 ± 4.1 vs 56.8 ± 3.7 pixels) (P < 0.001), VEGF (19.53 ± 3.2 vs 34.9 ± 4.7 pixels) (P < 0.05) and NTT (21.84 ± 0.7 vs 39.01 ± 4.0 pixels) (P < 0.05) evaluated by immunohistochemistry were also reduced in PPVL + NAC animals. Also, when evaluated by Western blot eNOS expression (0.32 ± 0.03 vs 0.39 ± 0.03 a.μ) (P < 0.05) and VEGF expression (0.31 ± 0.09 vs 0.38 ± 0.04 a.μ) (P < 0.01). Furthermore, NAC modulated DNA damage in PPVL + NAC animals.
CONCLUSION: In view of these results, we believe NAC is able to protect the stomach from the alterations induced by the PPVL procedure.
Collapse
|
|
48
|
Abstract
Patients with cirrhosis and portal hypertension are at an increased risk of the development of circulatory dysfunction that may potentially result in multiple organ failure. Apart from the liver, this may involve the heart, lungs, kidneys, the immune system, the adrenal glands, and other organ systems. As the disease progresses, the circulation becomes hyperdynamic, and signs of cardiac, pulmonary, and renal dysfunction are observed, in addition to reduced survival. Infections and an altered cardiac function known as cirrhotic cardiomyopathy may be precipitators for the development of other complications such as hepatorenal syndrome. In patients with chronic organ dysfunction, various precipitating events may induce an acute-on-chronic renal failure and acute-on-chronic liver failure that negatively affect the prognosis. Future research on the pathophysiologic mechanisms of the complications and the precipitating factors is essential to understand the basics of the treatment of these challenging conditions. The aim of the present review is to focus on the development and precipitating factors of various organ failures in patients with decompensated cirrhosis.
Collapse
|
|
49
|
Hsu SJ, Wang SS, Huo TI, Lee FY, Huang HC, Chang CC, Hsin IF, Ho HL, Lin HC, Lee SD. The Impact of Spironolactone on the Severity of Portal-Systemic Collaterals and Hepatic Encephalopathy in Cirrhotic Rats. J Pharmacol Exp Ther 2015; 355:117-24. [PMID: 26260462 DOI: 10.1124/jpet.115.225516] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Accepted: 08/03/2015] [Indexed: 12/23/2022] Open
Abstract
Liver cirrhosis and portal hypertension are accompanied by portal-systemic collaterals formation and lethal complications. Angiogenesis participates in the development of collaterals. Spironolactone is an aldosterone receptor antagonist used to control fluid overload in cirrhotic patients although recent studies suggest that it also inhibits angiogenesis. This study investigated the effect of spironolactone on abnormal angiogenesis and portal-systemic collaterals in cirrhosis. Liver cirrhosis was induced in Sprague-Dawley rats by common bile duct ligation (BDL), and sham-operated rats were the controls. The BDL and sham rats received spironolactone (20 mg/kg/d, oral gavage) or vehicle from day 15 to 28 after the operations. Spironolactone did not influence the portal and systemic hemodynamic, and the renal and hepatic biochemistry data, but it significantly ameliorated hepatic fibrosis, portal-systemic shunting, and mesenteric angiogenesis. Plasma vascular endothelial growth factor (VEGF) levels and the mesenteric protein expression of VEGF and phosphor-vascular endothelial growth factor receptor 2 (VEGFR-2) decreased in the spironolactone group. Spironolactone did not affect motor activity or plasma ammonia levels. The down-regulation of VEGF pathway participates, albeit partly, in the antiangiogenic effect of spironolactone. Thus, spironolactone treatment in patients with liver cirrhosis may provide additional benefits aside from ascites control.
Collapse
Affiliation(s)
- Shao-Jung Hsu
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
| | - Sun-Sang Wang
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
| | - Teh-Ia Huo
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
| | - Fa-Yauh Lee
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
| | - Hui-Chun Huang
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
| | - Ching-Chih Chang
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
| | - I-Fang Hsin
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
| | - Hsin-Ling Ho
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
| | - Han-Chieh Lin
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
| | - Shou-Dong Lee
- Faculty of Medicine (S.-J.H., S.-S.W., F.-Y.L., H.-C.H., C.-C.C., I-F.H., H.-C.L., S.-D.L.) and Institute of Pharmacology (S.-J.H., T.-I.H., I-F.H., H.-L.H.), School of Medicine, National Yang-Ming University; Division of Gastroenterology (S.-J.H., T.-I.H., F.-Y.L., H.-C.H., H.-L.H., H.-C.L.) and General Medicine, Department of Medicine (C.-C.C.), Endoscopy Center for Diagnosis and Treatment (I-F.H.), and Department of Medical Affairs and Planning (S.-S.W.), Taipei Veterans General Hospital; and Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital (S.-D.L.), Taipei, Taiwan
| |
Collapse
|
|
50
|
Bocca C, Novo E, Miglietta A, Parola M. Angiogenesis and Fibrogenesis in Chronic Liver Diseases. Cell Mol Gastroenterol Hepatol 2015; 1:477-488. [PMID: 28210697 PMCID: PMC5301407 DOI: 10.1016/j.jcmgh.2015.06.011] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 06/02/2015] [Indexed: 12/12/2022]
Abstract
Pathologic angiogenesis appears to be intrinsically associated with the fibrogenic progression of chronic liver diseases, which eventually leads to the development of cirrhosis and related complications, including hepatocellular carcinoma. Several laboratories have suggested that this association is relevant for chronic liver disease progression, with angiogenesis proposed to sustain fibrogenesis. This minireview offers a synthesis of relevant findings and opinions that have emerged in the last few years relating liver angiogenesis to fibrogenesis. We discuss liver angiogenesis in normal and pathophysiologic conditions with a focus on the role of hypoxia and hypoxia-inducible factors and assess the evidence supporting a clear relationship between angiogenesis and fibrogenesis. A section is dedicated to the critical interactions between liver sinusoidal endothelial cells and either quiescent hepatic stellate cells or myofibroblast-like stellate cells. Finally, we introduce the unusual, dual (profibrogenic and proangiogenic) role of hepatic myofibroblasts and emerging evidence supporting a role for specific mediators like vasohibin and microparticles and microvesicles.
Collapse
Key Words
- ANGPTL3, angiopoietin-like-3 peptide
- Akt, protein kinase B
- Ang-1, angiopoietin-1
- CCL2, chemokine ligand 2
- CCR, chemokine receptor
- CLD, chronic liver disease
- ET-1, endothelin 1
- HCC, hepatocellular carcinoma
- HIF, hypoxia-inducible factor
- HSC, hepatic stellate cell
- HSC/MFs, myofibroblast-like cells from activated hepatic stellate cells
- Hh, Hedgehog
- Hypoxia
- LSEC, liver sinusoidal endothelial cell
- Liver Angiogenesis
- Liver Fibrogenesis
- MF, myofibroblast
- MP, microparticle
- Myofibroblasts
- NAFLD, nonalcoholic fatty liver disease
- NASH, nonalcoholic steatohepatitis
- NO, nitric oxide
- PDGF, platelet-derived growth factor
- ROS, reactive oxygen species
- VEGF, vascular endothelial growth factor
- VEGF-R2, vascular endothelial growth factor receptor type 2
- eNOS, endothelial nitric oxide synthase
- α-SMA, α-smooth muscle actin
Collapse
Affiliation(s)
| | | | | | - Maurizio Parola
- Unit of Experimental Medicine and Clinical Pathology, Department of Clinical and Biological Sciences, School of Medicine, University of Torino, Torino, Italy
| |
Collapse
|