|
1
|
Maimaitiaishan T, Cheng J, Wang X, Chen L. Reply to Comments on 'Technical Note on Modified Direct Intrahepatic Portocaval Shunt Targeting Different Vessels for Portal Vein Obstruction in Cirrhosis'. Cardiovasc Intervent Radiol 2025; 48:711-712. [PMID: 40169439 DOI: 10.1007/s00270-025-04026-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Accepted: 03/20/2025] [Indexed: 04/03/2025]
Affiliation(s)
- Tangnuer Maimaitiaishan
- Department of Gastroenterology and Hepatology, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuchang District, Wuhan, 430071, Hubei Province, China
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, China
| | - Jie Cheng
- Department of Gastroenterology and Hepatology, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuchang District, Wuhan, 430071, Hubei Province, China
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, China
| | - Xiaobing Wang
- Department of Gastroenterology and Hepatology, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuchang District, Wuhan, 430071, Hubei Province, China.
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, China.
| | - Liping Chen
- Department of Gastroenterology and Hepatology, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuchang District, Wuhan, 430071, Hubei Province, China.
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, China.
| |
Collapse
|
|
2
|
Chan LL, Chan SL. Future perspectives on immunotherapy for hepatocellular carcinoma. Ther Adv Med Oncol 2025; 17:17588359251323199. [PMID: 40144682 PMCID: PMC11938898 DOI: 10.1177/17588359251323199] [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: 10/26/2024] [Accepted: 02/05/2025] [Indexed: 03/28/2025] Open
Abstract
In recent years, several global phase III trials have shown that combinations of immune checkpoint inhibitors (ICIs) offer superior efficacy and survival compared to multi-kinase inhibitors, establishing them as the gold standard for treating patients with advanced hepatocellular carcinoma (HCC). This success has led to investigations into expanding the use of immunotherapy into various other settings and populations, including neoadjuvant and adjuvant therapies, patients with decompensated liver function and those awaiting liver transplantation. Despite its proven efficacy, a significant number of patients still develop resistance to immunotherapy, highlighting the need for innovative strategies to address this challenge. Approaches aimed at enhancing tumour immunogenicity, such as combining immunotherapy with transarterial chemoembolization or radiation therapies, show significant promise. Additionally, novel immunotherapeutics - such as triplet therapy, bispecific antibodies, adoptive T-cell therapy and cancer vaccines - are in early development for HCC. These agents have demonstrated potential for synergistic effects with existing ICIs, with initial studies yielding positive outcomes. In this review, we offer our future perspective on immunotherapy, emphasizing emerging indications, novel combination strategies and the development of new immunotherapeutic agents. Overall, the future of immunotherapy in HCC is brimming with extraordinary potential, set to transform the treatment landscape and redefine the possibilities for managing this challenging disease.
Collapse
Affiliation(s)
- Landon L. Chan
- State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Sir YK Pao Centre for Cancer, SIRT, Hong Kong Cancer Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Stephen L. Chan
- State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Sir YK Pao Centre for Cancer, SIRT, Hong Kong Cancer Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, Hong Kong, China
| |
Collapse
|
|
3
|
Matsui T, Nagai H, Mukozu T, Wakui N, Matsuda T, Igarashi Y. Variceal bleeding following treatment with atezolizumab plus bevacizumab in two patients with unresectable hepatocellular carcinoma. Clin J Gastroenterol 2024; 17:1058-1066. [PMID: 39152332 DOI: 10.1007/s12328-024-02031-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 08/07/2024] [Indexed: 08/19/2024]
Abstract
Bleeding-related adverse events may occur due to anti-vascular endothelial growth factors. Here, we report two cases of variceal rupture during atezolizumab plus bevacizumab (ATZ/BV) treatment for unresectable hepatocellular carcinoma (u-HCC).Case 1 involved a man in his 60 s with alcoholic liver cirrhosis (LC) and u-HCC. Seventy-four days after ATZ/BV administration, the patient was admitted for hematemesis. Upper esophagogastroduodenoscopy (EGD) revealed worsening of the esophageal varices (EVs) to F2 grade with active bleeding. Endoscopic variceal ligation successfully achieved hemostasis.Case 2 involved a man in his 70 s with alcoholic LC and u-HCC. The patient was admitted with hematemesis 114 days after ATZ/BV administration. During EGD, the EVs deteriorated to F3 grade, although hemostasis had already been achieved. The evaluation was discontinued during the observation stage because of the worsening hepatic reserve.Neither patient had EVs warranting prophylactic treatment before ATZ/BV administration, showed a partial tumor response, or had portal vein tumor thrombus. Both patients demonstrated increased total diameters of the collateral veins and splenic volume compared to those before treatment. These findings suggest that ATZ/BV treatment may increase portal pressure. In conclusion, the administration of ATZ/BV to patients with LC and u-HCC necessitates careful management of EVs aggravation and rupture.
Collapse
Affiliation(s)
- Teppei Matsui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan.
| | - Hidenari Nagai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Takanori Mukozu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Noritaka Wakui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Takahisa Matsuda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Yoshinori Igarashi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
| |
Collapse
|
|
4
|
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]
|
|
5
|
Shimizu R, Matsui T, Nagumo H, Kobayashi K, Ogino Y, Mukozu T, Wakui N, Nagai H. A case of hepatic encephalopathy in a patient with unresectable hepatocellular carcinoma and portal vein tumor thrombus successfully treated with shunt embolization and multimodal therapy. KANZO 2024; 65:81-91. [DOI: 10.2957/kanzo.65.81] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Affiliation(s)
- Riku Shimizu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University
| | - Teppei Matsui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University
| | - Hideki Nagumo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University
| | - Kojirou Kobayashi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University
- Division of Gastroenterology, Nissan Tamagawa Hospital
| | - Yu Ogino
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University
| | - Takanori Mukozu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University
| | - Noritaka Wakui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University
| | - Hidenari Nagai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University
| |
Collapse
|
|
6
|
Noah AA, El-Mezayen NS, El-Ganainy SO, Darwish IE, Afify EA. Reversal of fibrosis and portal hypertension by Empagliflozin treatment of CCl 4-induced liver fibrosis: Emphasis on gal-1/NRP-1/TGF-β and gal-1/NRP-1/VEGFR2 pathways. Eur J Pharmacol 2023; 959:176066. [PMID: 37769984 DOI: 10.1016/j.ejphar.2023.176066] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/06/2023] [Accepted: 09/19/2023] [Indexed: 10/03/2023]
Abstract
To date, liver fibrosis has no clinically approved treatment. Empagliflozin (EMPA), a highly selective sodium-glucose-cotransporter-2 (SGLT2) inhibitor, has shown ameliorative potential in liver diseases without revealing its full mechanisms. Neuropilin-1 (NRP-1) is a novel regulator of profibrogenic signaling pathways related to hepatic stellate cells (HSCs) and hepatic sinusoidal endothelial cells (HSECs) that modulates intrahepatic profibrogenic and angiogenic pathways. Herein, EMPA's antifibrotic potentials and effects on galactin-1 (Gal-1)/NRP-1 signaling pathways have been evaluated in an experimental liver fibrosis rat model by testing different EMPA dose regimens. EMPA treatment brought a dose-dependent decrease in Gal-1/NRP-1 hepatic expression. This was coupled with suppression of major HSCs pro-fibrotic pathways; transforming growth factor-β (TGF-β)/TGF-βRI/Smad2 and platelet-derived growth factor-beta (PDGF-β) with a diminution of hepatic Col 1A1 level. In addition, EMPA prompted a protuberant suppression of the angiogenic pathway; vascular endothelial growth factor (VEGF)/VEGF-receptor-2 (VEGFR-2)/SH2-Domain Containing Adaptor Protein-B (Shb), and reversal of altered portal hypertension (PHT) markers; endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS). The amelioration of liver fibrosis was coupled with a remarkable improvement in liver aminotransferases and histologic hepatic fibrosis Ishak scores. The highest EMPA dose showed a good safety profile with minimal changes in renal function and glycemic control. Thus, the current study brought about novel findings for a potential liver fibrosis treatment modality via targeting NRP-1 signaling pathways by EMPA.
Collapse
Affiliation(s)
- Ashraf A Noah
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt; Clinical Research Administration, Alexandria Directorate of Health Affairs, Egyptian Ministry of Health and Population, Alexandria, Egypt
| | - Nesrine S El-Mezayen
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt.
| | - Samar O El-Ganainy
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt
| | - Inas E Darwish
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt; Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Elham A Afify
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| |
Collapse
|
|
7
|
Kikugawa C, Uchikawa S, Kawaoka T, Kinami T, Yano S, Amioka K, Naruto K, Ando Y, Yamaoka K, Tsuge M, Kosaka Y, Ohya K, Mori N, Takaki S, Tsuji K, Kouno H, Kohno H, Morio K, Moriya T, Nonaka M, Aisaka Y, Masaki K, Honda Y, Naeshiro N, Hiramatsu A, Aikata H, Oka S. Outcomes of Patients with Child-Pugh B and Unresectable Hepatocellular Carcinoma Undergoing First-Line Systemic Treatment with Sorafenib, Lenvatinib, or Atezolizumab Plus Bevacizumab. Oncology 2023; 102:239-251. [PMID: 37729889 DOI: 10.1159/000533859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 07/31/2023] [Indexed: 09/22/2023]
Abstract
INTRODUCTION Systemic therapy is recommended for patients with Child-Pugh A in hepatocellular carcinoma (HCC). We analyzed the outcomes of a cohort of patients with HCC who received either sorafenib (Sor), lenvatinib (Len) or atezolizumab plus bevacizumab (Atezo + Bev) as first-line systemic therapy for HCC, with the aim of identifying prognostic factors for survival. METHODS A total of 825 patients with advanced HCC and Child-Pugh A or B received either Sor, Len or Atezo + Bev as first-line systemic therapy. Liver function was assessed according to the Child-Pugh score and the modified albumin-bilirubin (mALBI) grade. RESULTS Prognosis was analyzed according to liver function such as Child-Pugh classifications, scores, and mALBI grades that worsened with a decline in liver function (p <0.001 for all). A Child-Pugh score of 7 was a factor significantly associated with OS. In patients with a Child-Pugh score of 7, an mALBI grade of 3 was an independent predictor of OS. In Child-Pugh B patients with HCC, receiving Atezo + Bev was identified as a factor associated with PFS. CONCLUSION Determining the hepatic reserve of patients with unresectable HCC might be useful for identifying patents suitable for systemic treatment for HCC. Atezo + Bev might prolong the PFS of patients with a Child-Pugh score of 7.
Collapse
Affiliation(s)
- Chihiro Kikugawa
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Higashihiroshima, Japan,
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Higashihiroshima, Japan,
| | - Shinsuke Uchikawa
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Higashihiroshima, Japan
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Higashihiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Higashihiroshima, Japan
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Higashihiroshima, Japan
| | - Takahiro Kinami
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Higashihiroshima, Japan
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Higashihiroshima, Japan
| | - Shigeki Yano
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Higashihiroshima, Japan
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Higashihiroshima, Japan
| | - Kei Amioka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Higashihiroshima, Japan
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Higashihiroshima, Japan
| | - Kensuke Naruto
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Higashihiroshima, Japan
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Higashihiroshima, Japan
| | - Yuwa Ando
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Higashihiroshima, Japan
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Higashihiroshima, Japan
| | - Kenji Yamaoka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Higashihiroshima, Japan
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Higashihiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Higashihiroshima, Japan
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Higashihiroshima, Japan
| | - Yumi Kosaka
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan
| | - Kazuki Ohya
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan
| | - Nami Mori
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan
| | - Shintaro Takaki
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan
| | - Keiji Tsuji
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan
| | - Hirotaka Kouno
- Department of Gastroenterology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Hiroshima, Japan
| | - Hiroshi Kohno
- Department of Gastroenterology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Hiroshima, Japan
| | - Kei Morio
- Department of Gastroenterology, Chugoku Rosai Hospital, Hiroshima, Japan
| | - Takashi Moriya
- Department of Gastroenterology, Chugoku Rosai Hospital, Hiroshima, Japan
| | - Michihiro Nonaka
- Department of Gastroenterology, JA Hiroshima General Hospital, Hiroshima, Japan
| | - Yasuyuki Aisaka
- Department of Gastroenterology, JA Hiroshima General Hospital, Hiroshima, Japan
| | - Keiichi Masaki
- Department of Gastroenterology, Hiroshima City Asa Citizens Hospital, Hiroshima, Japan
| | - Yohji Honda
- Department of Gastroenterology, Hiroshima City Asa Citizens Hospital, Hiroshima, Japan
| | - Noriaki Naeshiro
- Department of Gastroenterology, National Hospital Organization Higashihiroshima Medical Center, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology, Hiroshima Memorial Hospital, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology, Hiroshima Prefectural Hospital, Hiroshima, Japan
| | - Shiro Oka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Higashihiroshima, Japan
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Higashihiroshima, Japan
| |
Collapse
|
|
8
|
SENP6-Mediated deSUMOylation of VEGFR2 Enhances Its Cell Membrane Transport in Angiogenesis. Int J Mol Sci 2023; 24:ijms24032544. [PMID: 36768878 PMCID: PMC9916989 DOI: 10.3390/ijms24032544] [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: 12/22/2022] [Revised: 01/10/2023] [Accepted: 01/17/2023] [Indexed: 01/31/2023] Open
Abstract
Angiogenesis is a significant pathogenic characteristic of diabetic microangiopathy. Advanced glycation end products (AGEs) are considerably elevated in diabetic tissues and can affect vascular endothelial cell shape and function. Regulation of the vascular endothelial growth factor (VEGF)-VEGF receptor 2 (VEGFR2) signaling pathway is a critical mechanism in the regulation of angiogenesis, and VEGFR2 activity can be modified by post-translational changes. However, little research has been conducted on the control of small ubiquitin-related modifier (SUMO)-mediated VEGFR2 alterations. The current study investigated this using human umbilical vein endothelial cells (HUVECs) in conjunction with immunoblotting and immunofluorescence. AGEs increased Nrf2 translocation to the nucleus and promoted VEGFR2 expression. They also increased the expression of sentrin/SUMO-specific protease 6 (SENP6), which de-SUMOylated VEGFR2, and immunofluorescence indicated a reduction in VEGFR2 accumulation in the Golgi and increased VEGFR2 transport from the Golgi to the cell membrane surface via the coatomer protein complex subunit beta 2. VEGFR2 on the cell membrane was linked to VEGF generated by pericytes, triggering the VEGF signaling cascade. In conclusion, this study demonstrates that SENP6 regulates VEGFR2 trafficking from the Golgi to the endothelial cell surface. The SENP6-VEGFR2 pathway plays a critical role in pathological angiogenesis.
Collapse
|
|
9
|
Yi F, Guo X, Zeng QL, Yang B, He Y, Yuan S, Arora A, Qi X. Computed Tomography Images of Spontaneous Portosystemic Shunt in Liver Cirrhosis. Can J Gastroenterol Hepatol 2022; 2022:3231144. [PMID: 35719322 PMCID: PMC9200601 DOI: 10.1155/2022/3231144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 04/23/2022] [Accepted: 05/11/2022] [Indexed: 12/05/2022] Open
Abstract
Spontaneous portosystemic shunt (SPSS) refers to collateral vessels that communicate between the portal vein system and systemic circulation. SPSS mainly includes esophageal varices, gastric varices, left gastric vein, recanalized paraumbilical vein, abdominal wall varices, and spontaneous splenorenal shunt. SPSS contributes to the development of hepatic encephalopathy caused by portal vein inflow bypassing and carries a higher risk of death in liver cirrhosis. Abdominal contrast-enhanced computed tomography is a major imaging approach to establish a diagnosis of SPSS and evaluate its location and feature. This review primarily describes the main contrast-enhanced CT features of SPSS in liver cirrhosis.
Collapse
Affiliation(s)
- Fangfang Yi
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command (formerly called General Hospital of Shenyang Military Area), Shenyang 110840, China
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou 325006, China
| | - Xiaozhong Guo
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command (formerly called General Hospital of Shenyang Military Area), Shenyang 110840, China
| | - Qing-Lei Zeng
- Department of Infectious Diseases and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Benqiang Yang
- Department of Radiology, General Hospital of Northern Theater Command, Shenyang 110840, China
| | - Yanglan He
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command (formerly called General Hospital of Shenyang Military Area), Shenyang 110840, China
- Postgraduate College, China Medical University, Shenyang 110122, China
| | - Shanshan Yuan
- Department of Gastroenterology, Xi'an Central Hospital, Xi'an 710003, China
| | - Ankur Arora
- Department of Radiology, Royal Liverpool University Hospital, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
| | - Xingshun Qi
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command (formerly called General Hospital of Shenyang Military Area), Shenyang 110840, China
| |
Collapse
|
|
10
|
Hatanaka T, Kakizaki S, Nagashima T, Namikawa M, Ueno T, Tojima H, Takizawa D, Naganuma A, Arai H, Sato K, Harimoto N, Shirabe K, Uraoka T. Liver Function Changes in Patients with Hepatocellular Carcinoma Treated with Lenvatinib: Predictive Factors of Progression to Child-Pugh Class B, the Formation of Ascites and the Candidates for the Post-Progression Treatment. Cancers (Basel) 2020; 12:2906. [PMID: 33050527 PMCID: PMC7601832 DOI: 10.3390/cancers12102906] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 09/26/2020] [Accepted: 10/07/2020] [Indexed: 02/08/2023] Open
Abstract
The aim of this multicenter retrospective study was to assess the change in liver function in patients with hepatocellular carcinoma treated with lenvatinib. Among 139 consecutive patients receiving lenvatinib treatment between March 2018 and July 2019, 28 patients with Child-Pugh class B and one patient with inadequate patient information were excluded. Remaining 110 patients with Child-Pugh class A were analyzed. The median age of 110 patients was 73 years (IQR 66.7-80) and 88 patients (80.0%) were men. Child-Pugh score was 5 (CP5A) and 6 (CP6A) in 58 (52.7%) and 52 patients (47.3%), and ALBI grade was 1 and 2 in 38 (34.5%) and 72 patients (65.5%), respectively. The deterioration to Child-Pugh class B was found in 43 patients (39.1%) during the lenvatinib treatment. The favorable factors related to preserving liver function were significantly shown to be male, ALBI grade 1, CP5A and BCLC early or intermediate stage in the multivariate analysis. The formation of ascites was found in 32 patients (28.6%). The significant unfavorable factors associated with the formation of ascites were found to be low platelet count and CP6A. Among the 79 patients, there were 36 (45.6%) and 11 patients (13.9%) who fulfilled the criteria for candidate for the post-progression treatment and ramucirumab treatment, respectively. The predictive factors of the post-progression treatment were shown to be ALBI grade 1 and CP5A in multivariate analysis. In conclusion, male, ALBI grade 1, CP5A and BCLC early or intermediate stage were favorable factors related to sustaining liver function and the patients with ALBI grade 1 and CP5A were eligible for the post-progression treatment. Careful screening for ascites was needed in patients with low platelet count and CP6A.
Collapse
Affiliation(s)
- Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, 564-1 Kamishindenmachi, Maebashi, Gunma 371-0821, Japan
| | - Satoru Kakizaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa, Maebashi, Gunma 371-8511, Japan; (S.K.); (H.T.); (K.S.); (T.U.)
- Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki, Gunma 370-0829, Japan
| | - Tamon Nagashima
- Department of Gastroenterology, National Hospital Organization Shibukawa Medical Center, 383 Shirai, Shibukawa, Gunma 377-0280, Japan;
| | - Masashi Namikawa
- Department of Internal Medicine, Kiryu Kosei General Hospital, 6-6-3 Orihime-cho, Kiryu, Gunma 376-0024, Japan;
| | - Takashi Ueno
- Department of Internal Medicine, Isesaki Municipal Hospital, 12-1 Tsunatorihonmachi, Isesaki, Gunma 372-0817, Japan;
| | - Hiroki Tojima
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa, Maebashi, Gunma 371-8511, Japan; (S.K.); (H.T.); (K.S.); (T.U.)
| | - Daichi Takizawa
- Department of Gastroenterology, Maebashi Red Cross Hospital, 389-1 Asakuramachi, Maebashi, Gunma 371-0811, Japan; (D.T.); (H.A.)
| | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki, Gunma 370-0829, Japan;
| | - Hirotaka Arai
- Department of Gastroenterology, Maebashi Red Cross Hospital, 389-1 Asakuramachi, Maebashi, Gunma 371-0811, Japan; (D.T.); (H.A.)
| | - Ken Sato
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa, Maebashi, Gunma 371-8511, Japan; (S.K.); (H.T.); (K.S.); (T.U.)
| | - Norifumi Harimoto
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine, 3-39-15 Showa, Maebashi, Gunma 371-8511, Japan; (N.H.); (K.S.)
| | - Ken Shirabe
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine, 3-39-15 Showa, Maebashi, Gunma 371-8511, Japan; (N.H.); (K.S.)
| | - Toshio Uraoka
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa, Maebashi, Gunma 371-8511, Japan; (S.K.); (H.T.); (K.S.); (T.U.)
| |
Collapse
|
|
11
|
Hidaka H, Uojima H, Nakazawa T, Shao X, Hara Y, Iwasaki S, Wada N, Kubota K, Tanaka Y, Shibuya A, Kanoh Y, Kokubu S, Koizumi W. Portal hemodynamic effects of lenvatinib in patients with advanced hepatocellular carcinoma: A prospective cohort study. Hepatol Res 2020; 50:1083-1090. [PMID: 32515895 DOI: 10.1111/hepr.13531] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/16/2020] [Accepted: 05/31/2020] [Indexed: 02/08/2023]
Abstract
AIM Lenvatinib is an oral, multitargeted, tyrosine kinase inhibitor, which suppress tumor angiogenesis and tumor progression. It was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma (HCC). Sorafenib had a beneficial effect on portocollateral circulation with portal hypertension in translating and clinical studies. However, the hemodynamic effects of lenvatinib appear to be different from those of sorafenib because the efficacy of lenvatinib for vascular endothelial growth factor receptors and fibroblast growth factor receptors is different from that of sorafenib. This study was prospectively performed to evaluate the portal hemodynamic effect of lenvatinib in patients with advanced HCC using duplex Doppler ultrasonography. METHODS In total, 28 Child-Pugh class A or B patients with advanced HCC received lenvatinib depending on body weight daily for 2 weeks. Primary outcomes were changes in the hemodynamics of the portal venous system using duplex Doppler ultrasonography before and after the 2-week administration of lenvatinib. RESULTS The portal venous flow velocity (cm/s) significantly reduced (27 ± 12.1 vs. 22.6 ± 8.0, P = 0.019), while portal venous area (cm2 ) did not change after the 2-week administration (0.80 ± 0.36 vs. 0.82 ± 0.27, P = 0.665). Therefore, the congestion index (portal venous area/portal venous flow velocity), which reflects the pathophysiological hemodynamics of the portal venous system significantly worsened (0.037 ± 0.025 vs. 0.043 ± 0.024, P = 0.045). CONCLUSIONS Considering that this was a short-term study, because lenvatinib could be an agent that aggravates portal hypertension, it will be necessary to verify its clinical effects for portal hypertension in future studies.
Collapse
Affiliation(s)
- Hisashi Hidaka
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Haruki Uojima
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takahide Nakazawa
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Xue Shao
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.,Department of Hepatopancreatobiliary Medicine, Second Hospital, Jilin University, Changchun, China
| | - Yusuke Hara
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Shuichiro Iwasaki
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Naohisa Wada
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Kosuke Kubota
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yoshiaki Tanaka
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Akitaka Shibuya
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yuhsaku Kanoh
- Department of Laboratory Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Shigehiro Kokubu
- Institute for Liver Disease Minimal Invasive Treatment, Shin Yurigaoka General Hospital, Kawasaki, Kanagawa, Japan
| | - Wasaburo Koizumi
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| |
Collapse
|
|
12
|
Kuwahara A, Sasaki R, Fukushima M, Haraguchi M, Miuma S, Miyaaki H, Nakao K. Shunt occlusion prior to lenvatinib administration prevents hepatic encephalopathy and hyperammonemia. JGH Open 2020; 4:775-776. [PMID: 32782972 PMCID: PMC7411641 DOI: 10.1002/jgh3.12351] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 04/20/2020] [Accepted: 04/21/2020] [Indexed: 11/11/2022]
Affiliation(s)
- Ai Kuwahara
- Department of Gastroenterology and HepatologyNagasaki University Graduate School of Biomedical Sciences Nagasaki Japan
| | - Ryu Sasaki
- Department of Gastroenterology and HepatologyNagasaki University Graduate School of Biomedical Sciences Nagasaki Japan
| | - Masanori Fukushima
- Department of Gastroenterology and HepatologyNagasaki University Graduate School of Biomedical Sciences Nagasaki Japan
| | - Masafumi Haraguchi
- Department of Gastroenterology and HepatologyNagasaki University Graduate School of Biomedical Sciences Nagasaki Japan
| | - Satoshi Miuma
- Department of Gastroenterology and HepatologyNagasaki University Graduate School of Biomedical Sciences Nagasaki Japan
| | - Hisamitsu Miyaaki
- Department of Gastroenterology and HepatologyNagasaki University Graduate School of Biomedical Sciences Nagasaki Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and HepatologyNagasaki University Graduate School of Biomedical Sciences Nagasaki Japan
| |
Collapse
|
|
13
|
Ohya K, Kawaoka T, Namba M, Uchikawa S, Kodama K, Morio K, Nakahara T, Murakami E, Hiramatsu A, Tsuge M, Yamauchi M, Imamura M, Chayama K, Aikata H. Early changes in ammonia levels and liver function in patients with advanced hepatocellular carcinoma treated by lenvatinib therapy. Sci Rep 2019; 9:12101. [PMID: 31431642 PMCID: PMC6702170 DOI: 10.1038/s41598-019-48045-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 07/24/2019] [Indexed: 12/29/2022] Open
Abstract
We aimed to investigate the early changes in ammonia levels and liver function in patients with advanced hepatocellular carcinoma treated with lenvatinib. This retrospective study included 23 patients with advanced hepatocellular carcinoma who were able to receive lenvatinib continuously for at least 1 week. We compared their ammonia levels (NH3), total bilirubin (Bil), albumin, and prothrombin (PT) activity at before and after 1 week of lenvatinib administration, and additionally, compared the 2 groups which were divided based on the presence/absence of portosystemic collaterals (PSCs). Before administration of lenvatinib the patients with PSCs had significantly worse ammonia levels and liver function than the patients without PSCs (NH3: P = 0.013, Bil: P = 0.004, PT: P = 0.047, respectively). Moreover, the indices were worse in all the patients after 1 week of lenvatinib than before administration (NH3: P = 0.001, Bil: P = 0.025, PT: P < 0.001, respectively). Moreover, the changes in ammonia levels were investigated for 4 weeks. The ammonia level increased, to peak at 2 weeks, but decreased after 3 weeks. None of the patients discontinued lenvatinib therapy because of an adverse event. The ammonia levels of the study patients increased from baseline at 1 week after lenvatinib administration, but therapy could be continued for 4 weeks by appropriate management.
Collapse
Affiliation(s)
- Kazuki Ohya
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Maiko Namba
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Kenichiro Kodama
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan.
| |
Collapse
|
|
14
|
Namba M, Kawaoka T, Aikata H, Kodama K, Uchikawa S, Ohya K, Morio K, Fujino H, Nakahara T, Murakami E, Yamauchi M, Tsuge M, Hiramatsu A, Imamura M, Baba Y, Awai K, Chayama K. Percutaneous transvenous shunt occlusion for portosystemic encephalopathy due to lenvatinib administration to a patient with hepatocellular carcinoma and portosystemic shunt. Clin J Gastroenterol 2019; 12:341-346. [PMID: 30706429 DOI: 10.1007/s12328-019-00938-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 01/11/2019] [Indexed: 12/11/2022]
Abstract
We report a 74-year-old male patient with compensated cirrhosis after hepatic C virus eradication. After the patient underwent hepatectomy for hepatocellular carcinoma, multiple lung and lymph node metastases were detected by computed tomography. Computed tomography also revealed a portosystemic shunt from the superior mesenteric vein to the right testicular vein. He was administered lenvatinib (12 mg). Five days after the initiation of lenvatinib, he developed grade 3 hepatic encephalopathy, and his ammonia level increased. Lenvatinib was stopped, with improvement of the encephalopathy and decrease in ammonia level. When lenvatinib was restarted, grade 2 encephalopathy recurred which then improved upon stopping the drug. We thought that the encephalopathy was due to the portosystemic shunt, and occlusion of the shunt was performed. The day after shunt occlusion, lenvatinib (8 mg) was restarted, and the lenvatinib dose was increased to 12 mg at 2 days after shunt occlusion. Subsequently, the ammonia level remained stable and the patient remained alert and conscious. Lenvatinib was continued until the time of this report (40 days after shunt occlusion), and after 1 month of lenvatinib therapy, the computed tomography verified absence of the portosystemic shunt and stable disease of hepatocellular carcinoma.
Collapse
Affiliation(s)
- Maiko Namba
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan.
| | - Kenichiro Kodama
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Kazuki Ohya
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| | - Yasutaka Baba
- Diagnostic Radiology, Institute, Graduate School of Biomedical Science, Hiroshima University Hospital, Hiroshima, Japan
| | - Kazuo Awai
- Diagnostic Radiology, Institute, Graduate School of Biomedical Science, Hiroshima University Hospital, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8551, Japan
| |
Collapse
|
|
15
|
Wei Y, Chen X, Shen H, Wu W, Cao G, Chen W, Wang Y, Shen H, Yu S, Zhang J. P-Selectin Level at First and Third Day After Portal Hypertensive Splenectomy for Early Prediction of Portal Vein Thrombosis in Patients With Cirrhosis. Clin Appl Thromb Hemost 2018; 24:76S-83S. [PMID: 30033741 PMCID: PMC6714827 DOI: 10.1177/1076029618788180] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
We aimed to investigate the changes in p-selectin (p-sel), thrombus precursor protein, and D-dimer (D-D) in patients with cirrhosis after portal hypertensive splenectomy and explore its values on the prediction of postoperative portal vein thrombosis (PVT) formation. A total of 144 patients with cirrhosis with portal hypertension who underwent portal hypertensive splenectomy from January 2009 to December 2016 were enrolled in this study and divided into the thrombus and nonthrombus groups. The levels of p-sel, thrombus precursor protein (TpP), and D-D were measured by flow cytometry, enzyme-linked immunosorbent assay, and immunoturbidimetry, respectively. Sensitivity, specificity, and other values for p-sel, TpP, and D-D were calculated. The linear discriminant, logistic regression, and decision tree methods were used to analyze the p-sel value on the prediction of PVT formation. Seventy-nine patients were confirmed having postoperative PVT, with the incidence rate of 54.86%. No significant differences were observed in the p-sel, TpP, and D-D between the thrombus and nonthrombus groups before surgery, but these 3 indexes were obviously elevated in the thrombus group after operation (P < .01). P-selectin level on first day showed the highest positive predictive value (91.0%) and diagnostic coincidence rate (83.3%), while negative expected value (76.6%) was lower than those of TpP and D-D. Multiple analyses showed the prediction accuracy of PVT was 61.1% (P = .023), 97.2% (P < .001), and 97.2% (P < .001), respectively. P-selectin has a significant value in predicting PVT. P-selectin level on first and third day is valuable and feasible for the early prediction of PVT.
Collapse
Affiliation(s)
- Yunhai Wei
- Surgical Department, Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Huzhou, People's Republic of China
| | - Xuedong Chen
- School of Science, Huzhou University, Huzhou, People's Republic of China
| | - Huaping Shen
- Surgical Department, Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Huzhou, People's Republic of China
| | - Wanbo Wu
- Surgical Department, Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Huzhou, People's Republic of China
| | - Guoliang Cao
- Surgical Department, Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Huzhou, People's Republic of China
| | - Wenxian Chen
- Surgical Department, Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Huzhou, People's Republic of China
| | - Yan Wang
- Surgical Department, Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Huzhou, People's Republic of China
| | - Hua Shen
- Surgical Department, Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Huzhou, People's Republic of China
| | - Sheng Yu
- Surgical Department, Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Huzhou, People's Republic of China
| | - Jinyu Zhang
- Surgical Department, Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Huzhou, People's Republic of China
| |
Collapse
|
|
16
|
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
|
|
17
|
Philips CA, Arora A, Shetty R, Kasana V. A Comprehensive Review of Portosystemic Collaterals in Cirrhosis: Historical Aspects, Anatomy, and Classifications. Int J Hepatol 2016; 2016:6170243. [PMID: 28074159 PMCID: PMC5198179 DOI: 10.1155/2016/6170243] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 11/01/2016] [Accepted: 11/17/2016] [Indexed: 02/07/2023] Open
Abstract
Portosystemic collateral formation in cirrhosis plays an important part in events that define the natural history in affected patients. A detailed understanding of collateral anatomy and hemodynamics in cirrhotics is essential to envisage diagnosis, management, and outcomes of portal hypertension. In this review, we provide detailed insights into the historical, anatomical, and hemodynamic aspects to portal hypertension and collateral pathways in cirrhosis with emphasis on the various classification systems.
Collapse
Affiliation(s)
- Cyriac Abby Philips
- Department of Hepatology and Transplant Medicine, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi 110070, India
| | - Ankur Arora
- Department of Radiodiagnosis, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi 110070, India
| | - Rajesh Shetty
- Department of Radiodiagnosis, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi 110070, India
| | - Vivek Kasana
- Department of Radiodiagnosis, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi 110070, India
| |
Collapse
|
|
18
|
YOU QI, KONG LINGJIAN, LI FENGDONG, WANG HANGYU, LIU DIANGANG, PEI FENGHUA, SONG JITAO, XU JUN, CHEN JING. Human recombinant endostatin Endostar attenuates hepatic sinusoidal endothelial cell capillarization in CCl4-induced fibrosis in mice. Mol Med Rep 2015; 12:5594-600. [DOI: 10.3892/mmr.2015.4103] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Accepted: 06/23/2015] [Indexed: 11/06/2022] Open
|
|
19
|
Hepatic proliferation and angiogenesis markers are increased after portal deprivation in rats: a study of molecular, histological and radiological changes. PLoS One 2015; 10:e0125493. [PMID: 26020934 PMCID: PMC4447332 DOI: 10.1371/journal.pone.0125493] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2014] [Accepted: 03/03/2015] [Indexed: 01/11/2023] Open
Abstract
Background & Aims To determine the pathogenesis of liver nodules, and lesions similar to obliterative portal venopathy, observed after portosystemic shunts or portal vein thrombosis in humans. Methods We conducted an experimental study comparing portacaval shunt (PCS), total portal vein ligation (PVL), and sham (S) operated rats. Each group were either sacrificed at 6 weeks (early) or 6 months (late). Arterial liver perfusion was studied in vivo using CT, and histopathological changes were noted. Liver mRNA levels were quantified by RT-QPCR for markers of inflammation (Il10, Tnfa), proliferation (Il6st, Mki67, Hgf, Hnf4a), angiogenesis: (Vegfa, Vegfr 1, 2 and 3; Pgf), oxidative stress (Nos2, and 3, Hif1a), and fibrosis (Tgfb). PCS and PVL were compared to the S group. Results Periportal fibrosis and arterial proliferation was observed in late PCS and PVL groups. CT imaging demonstrated increased arterial liver perfusion in the PCS group. RT-QPCR showed increased inflammatory markers in PCS and PVL early groups. Tnfa and Il10 were increased in PCS and PVL late groups respectively. All proliferative markers increased in the PCS, and Hnf4a in the PVL early groups. Mki67 and Hnf4a were increased in the PCS late group. Nos3 was increased in the early and late PCS groups, and Hif1a was decreased in the PVL groups. Markers of angiogenesis were all increased in the early PCS group, and Vegfr3 and Pgf in the late PCS group. Only Vegfr3 was increased in the PVL groups. Tgf was increased in the PCS groups. Conclusions Portal deprivation in rats induces a sustained increase in intrahepatic markers of inflammation, angiogenesis, proliferation, and fibrosis.
Collapse
|
|
20
|
Philips CA, Anand L, Kumar KNC, Kasana V, Arora A. Rare, spontaneous trans-splenic shunt and intra-splenic collaterals with attendant splenic artery aneurysms in an adult patient with compensated cirrhosis and portal hypertension. Gastroenterol Rep (Oxf) 2015; 3:162-166. [PMID: 25008262 PMCID: PMC4423456 DOI: 10.1093/gastro/gou047] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 06/11/2014] [Accepted: 06/21/2014] [Indexed: 01/17/2023] Open
Abstract
We present a rare case of spontaneous trans-splenic shunt and intra-splenic collaterals in a patient with liver cirrhosis and portal hypertension. The shunt and presence of cirrhosis and portal hypertension was incidentally detected by abdominal computed tomographic imaging during evaluation for abdominal pain. There has been a single report on the presence of trans-splenic shunt in two children with extra-hepatic portal venous obstruction but no cases that report intra-splenic collaterals: to the best of our knowledge, this is the first reported case of spontaneous trans-splenic shunt in the presence of intra-splenic collaterals and incidental multiple splenic artery aneurysms that developed in an adult with compensated cirrhosis and portal hypertension.
Collapse
Affiliation(s)
- Cyriac Abby Philips
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India and Department of Radiology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Lovkesh Anand
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India and Department of Radiology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - K N Chandan Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India and Department of Radiology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Vivek Kasana
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India and Department of Radiology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ankur Arora
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India and Department of Radiology, Institute of Liver and Biliary Sciences, New Delhi, India
| |
Collapse
|
|
21
|
Theodorakis NG, Wang YN, Korshunov VA, Maluccio MA, Skill NJ. Thalidomide ameliorates portal hypertension via nitric oxide synthase independent reduced systolic blood pressure. World J Gastroenterol 2015; 21:4126-4135. [PMID: 25892862 PMCID: PMC4394073 DOI: 10.3748/wjg.v21.i14.4126] [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: 06/12/2014] [Revised: 07/30/2014] [Accepted: 10/15/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: Portal hypertension is a common complication of liver cirrhosis and significantly increases mortality and morbidity. Previous reports have suggested that the compound thalidomide attenuates portal hypertension (PHT). However, the mechanism for this action is not fully elucidated. One hypothesis is that thalidomide destabilizes tumor necrosis factor α (TNFα) mRNA and therefore diminishes TNFα induction of nitric oxide synthase (NOS) and the production of nitric oxide (NO). To examine this hypothesis, we utilized the murine partial portal vein ligation (PVL) PHT model in combination with endothelial or inducible NOS isoform gene knockout mice.
METHODS: Wild type, inducible nitric oxide synthase (iNOS)-/- and endothelial nitric oxide synthase (eNOS)-/- mice received either PVL or sham surgery and were given either thalidomide or vehicle. Serum nitrate (total nitrate, NOx) was measured daily for 7 d as a surrogate of NO synthesis. Serum TNFα level was quantified by enzyme-linked immunosorbent assay. TNFα mRNA was quantified in liver and aorta tissue by reverse transcription-polymerase chain reaction. PHT was determined by recording splenic pulp pressure (SPP) and abdominal aortic flow after 0-7 d. Response to thalidomide was determined by measurement of SPP and mean arterial pressure (MAP).
RESULTS: SPP, abdominal aortic flow (Qao) and plasma NOx were increased in wild type and iNOS-/- PVL mice when compared to sham operated control mice. In contrast, SPP, Qao and plasma NOx were not increased in eNOS-/- PVL mice when compared to sham controls. Serum TNFα level in both sham and PVL mice was below the detection limit of the commercial ELISA used. Therefore, the effect of thalidomide on serum TNFα levels was undetermined in wild type, eNOS-/- or iNOS-/- mice. Thalidomide acutely increased plasma NOx in wild type and eNOS-/- mice but not iNOS-/- mice. Moreover, thalidomide temporarily (0-90 min) decreased mean arterial pressure, SPP and Qao in wild type, eNOS-/- and iNOS-/- PVL mice, after which time levels returned to the respective baseline.
CONCLUSION: Thalidomide does not reduce portal pressure in the murine PVL model by modulation of NO biosynthesis. Rather, thalidomide reduces PHT by decreasing MAP by an undetermined mechanism.
Collapse
|
|
22
|
Sharma M, Rameshbabu CS. Collateral pathways in portal hypertension. J Clin Exp Hepatol 2012; 2:338-52. [PMID: 25755456 PMCID: PMC3940321 DOI: 10.1016/j.jceh.2012.08.001] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2012] [Accepted: 08/16/2012] [Indexed: 12/12/2022] Open
Abstract
Presence of portosystemic collateral veins (PSCV) is common in portal hypertension due to cirrhosis. Physiologically, normal portosystemic anastomoses exist which exhibit hepatofugal flow. With the development of portal hypertension, transmission of backpressure leads to increased flow in these patent normal portosystemic anastomoses. In extrahepatic portal vein obstruction collateral circulation develops in a hepatopetal direction and portoportal pathways are frequently found. The objective of this review is to illustrate the various PSCV and portoportal collateral vein pathways pertinent to portal hypertension in liver cirrhosis and EHPVO.
Collapse
Key Words
- AIPDV, anterior inferior pancreatico duodenal vein
- ASPDV, anterior superior pancreatico duodenal vein
- AV, azygos vein
- BCS, Budd–Chiari syndrome
- CBD, common bile duct
- CT, computed tomography
- DV, duodenal varices
- ECD, epicholedochal
- EHPVO, extrahepatic portal vein obstruction
- ERVP, extrinsic rectal venous plexus
- FJT, first jejunal trunk
- GEV, gastroepiploeic vein
- GT, gastrocolic trunk
- GV, gastric varices
- IMV, inferior mesenteric vein
- IPDV, inferior pancreatico duodenal vein
- IRV, inferior rectal veins
- IRVP, intrinsic rectal venous plexus
- IVC, inferior vena cava
- LGEV, left gastroepiploic vein
- LGV, left gastric vein
- LPV, left portal vein
- MCV, middle colic vein
- PACD, paracholedochal
- PHB, portal hypertensive biliopathy
- PIPDV, posterior inferior pancreatico duodenal vein
- PPCV, portoportal collateral vein
- PSCV, portosystemic collateral veins
- PSPDV, posterior superior pancreatico duodenal vein
- PUV, paraumbilical vein
- PV, portal vein
- PVT, portal vein thrombosis
- RGEV, right gastroepiploic
- RGV, right gastric vein
- SMV, superior mesenteric vein
- SRV, superior rectal vein
- SV, splenic vein
- SVC, superior vena cava
- US, ultrasonography
- collateral pathways
- portal hypertension
- varices
Collapse
Affiliation(s)
- Malay Sharma
- Jaswant Rai Speciality Hospital, Saket, Meerut 250 001, Uttar Pradesh, India
| | | |
Collapse
|
|
23
|
Moubarak E, Bouvier A, Boursier J, Lebigot J, Ridereau-Zins C, Thouveny F, Willoteaux S, Aubé C. Portosystemic collateral vessels in liver cirrhosis: a three-dimensional MDCT pictorial review. Abdom Radiol (NY) 2012; 37:746-66. [PMID: 22002160 DOI: 10.1007/s00261-011-9811-0] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE Portosystemic collateral vessels (PSCV) are a consequence of the portal hypertension that occurs in chronic liver diseases. Their prognosis is strongly marked by the risk of digestive hemorrhage and hepatic encephalopathy. MATERIALS AND METHODS CT was performed with a 16-MDCT scanner. Maximum intensity projection and volume rendering were systematically performed on a workstation to analyze PSCV. RESULTS We describe the PSCV according to their drainage into either the superior or the inferior vena cava. In the superior vena cave group, we found gastric veins, gastric varices, esophageal, and para-esophageal varices. In the inferior vena cava group, the possible PSCV are numerous, with different sub groups: gastro and spleno renal shunts, paraumbilical and abdominal wall veins, retroperitoneal shunts, mesenteric varices, gallbladder varices, and omental collateral vessels. Regarding clinical consequences esophageal and gastric varices are most frequently involved in digestive bleeding; splenorenal shunts often lead to hepatic encephalopathy; the paraumbilical vein is an acceptable derivation pathway for natural decompression of the portal system. CONCLUSION Knowledge of precise cartography of PSCV is essential to therapeutic decisions. MDCT is the best way to understand and describe the different types of PSCV.
Collapse
Affiliation(s)
- Elie Moubarak
- Department of Radiology, Angers University Hospital, Angers, France
| | | | | | | | | | | | | | | |
Collapse
|
|
24
|
He XJ, Huang TZ, Wang PJ, Peng XC, Li WC, Wang J, Tang J, Feng N, Yu MH. Morphological and biomechanical remodeling of the hepatic portal vein in a swine model of portal hypertension. Ann Vasc Surg 2011; 26:259-67. [PMID: 22192237 DOI: 10.1016/j.avsg.2011.10.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2011] [Revised: 10/09/2011] [Accepted: 10/17/2011] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To obtain the morphological and biomechanical remodeling of portal veins in swine with portal hypertension (PHT), so as to provide some mechanical references and theoretical basis for clinical practice about PHT. METHODS Twenty white pigs were used in this study, 14 of them were subjected to both carbon tetrachloride- and pentobarbital-containing diet to induce experimental liver cirrhosis and PHT, and the remaining animals served as the normal controls. The morphological remodeling of portal veins was observed. Endothelial nitric oxide synthase expression profile in the vessel wall was assessed at both mRNA and protein level. The biomechanical changes of the hepatic portal veins were evaluated through assessing the following indicators: the incremental elastic modulus, pressure-strain elastic modulus, volume elastic modulus, and the incremental compliance. RESULTS The swine PHT model was successfully established. The percentages for the microstructural components and the histological data significantly changed in the experimental group. Endothelial nitric oxide synthase expression was significantly downregulated in the portal veins of the experimental group. Three incremental elastic moduli (the incremental elastic modulus, pressure-strain elastic modulus, and volume elastic modulus) of the portal veins from PHT animals were significantly larger than those of the controls (P < 0.05), whereas the incremental compliance of hepatic portal vein decreased. CONCLUSIONS Our study suggests that the morphological and biomechanical properties of swine hepatic portal veins change significantly during the PHT process, which may play a critical role in the development of PHT and serve as potential therapeutic targets during clinical practice.
Collapse
Affiliation(s)
- Xi-Ju He
- Laboratory of Biomechanics, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Chan CC, Tsai SC, Cheng LY, Lee FY, Lin HC. Hemodynamic assessment of the development of portal-systemic collaterals in portal hypertensive rats. Dig Dis Sci 2011; 56:417-24. [PMID: 20635149 DOI: 10.1007/s10620-010-1302-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2009] [Accepted: 06/14/2010] [Indexed: 12/19/2022]
Abstract
BACKGROUND Portal hypertension induced the formation of portal-systemic collaterals. Revealing the developmental change of portal-systemic collaterals is important for future therapy. METHODS We observed the evolution of an accessible shunting vessel, the spleno-renal shunt (SRS), in rats after induction of portal hypertension by partial portal vein ligation (PVL). The hemodynamic and histological assessments of SRS were performed by transit time ultrasound and immunohistochemical studies. RESULTS The portal pressure of PVL rats surged to 16.5 ± 1.1 mmHg on day 1 after ligation surgery and was maintained at a significantly higher level (13.0 ± 0.4 mmHg) to day 14 when compared to sham rats (p < 0.05). The size or flow of SRS in PVL rats did not change immediately after portal pressure surge. Instead, they increased rapidly on day 4, peaked on day 7, and stabilized thereafter. The size and flow were greater and the resistance of SRS was lower in PVL rats after day 7 (p < 0.05). The anti-Ki67 immunohistochemical study demonstrated positive staining of endothelium in SRS and negative in portal vein or aorta of PVL rats. In addition, the endothelial cells of SRS were stained positive for CD31 and KLF5. CONCLUSIONS We concluded that the pressure-induced opening of pre-existing vessels was not the primary underlying mechanism in the formation of SRS. Endothelial proliferating and vascular remodeling process participated actively during the development of SRS. These observations can be used for studying the pathogenesis and developing more effective anti-portal hypertensive therapy in the future.
Collapse
Affiliation(s)
- Che-Chang Chan
- Division of Gastroenterology, Taipei Veterans General Hospital, Beitou District, Taipei city, Taiwan, Republic of China.
| | | | | | | | | |
Collapse
|
|
26
|
Li BY, Wang LN, Yue XQ, Li B. [Characteristics of sublingual vein and expressions of vascular endothelial growth factor and hypoxia-inducible factor 1alpha proteins in sublingual tissues of Beagle dogs with portal hypertension]. ACTA ACUST UNITED AC 2009; 7:463-7. [PMID: 19435562 DOI: 10.3736/jcim20090512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVE To observe sublingual vein characteristics and the expressions of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1alpha (HIF-1alpha) proteins in sublingual tissues of Beagle dogs with cirrhotic portal hypertension. METHODS Twelve Beagle dogs were randomly divided into normal control group and cirrhotic portal hypertension group. There were 6 dogs in each group. A canine model of cirrhosis portal hypertension was established by injecting dimethylnitrosamine (DMN) into portal vein once a week for 7 weeks. The characteristics of sublingual vein were observed. Portal venous pressure was measured by using bioelectric recording techniques. The expressions of VEGF and HIF-1alpha proteins in sublingual vein were detected by immunohistochemical method. RESULTS The shape and color of sublingual vein in beagle dogs in the cirrhotic portal hypertension group changed obviously as compared with the normal control group. Immunohistochemical results showed that there were almost no expressions of VEGF and HIF-1alpha proteins in sublingual tissues in the normal control group; however, the expressions of VEGF and HIF-1alpha proteins in sublingual tissues in the cirrhotic portal hypertension group significantly increased. CONCLUSION Changes of portal pressure may lead to the formation of the abnormal sublingual vein by increasing the expressions of VEGF and HIF-1alpha proteins in sublingual tissues in Beagle dogs with portal hypertension.
Collapse
Affiliation(s)
- Bai-yu Li
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | | | | | | |
Collapse
|
|
27
|
Abstract
The process of blood vessel proliferation, known as angiogenesis, is essential during embryonic development and organogenesis. In adult life, it participates in normal tissue repair, wound healing, and cyclical growth of the corpus luteum and the endometrium. Crucial as it is, angiogenesis can become pathological, and abnormal angiogenesis contributes to the pathogenesis of inflammatory and neoplasic diseases. The present review highlights the evidence for the role of angiogenesis in HCC (hepatocellular carcinoma) and discusses the increasing importance of inhibitors of angiogenesis in HCC therapy.
Collapse
|
|
28
|
Méndez-López M, Méndez M, Sánchez-Patán F, Casado I, Aller MA, López L, Corcuera MT, Alonso MJ, Nava MP, Arias J, Arias JL. Partial portal vein ligation plus thioacetamide: a method to obtain a new model of cirrhosis and chronic portal hypertension in the rat. J Gastrointest Surg 2007; 11:187-94. [PMID: 17390171 DOI: 10.1007/s11605-006-0063-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
To obtain a new model of chronic portal hypertension in the rat, two classical methods to produce portal hypertension, partial portal vein ligation and the oral administration of thioacetamide (TAA), have been combined. Male Wistar rats were divided into four groups: 1 (control; n = 10), 2 [triple partial portal vein ligation (TPVL); n = 9], 3 (TAA; n = 11), and 4 (TPVL plus TAA; n = 9). After 3 months, portal pressure, types of portosystemic collateral circulation, laboratory hepatic function tests (aspartate aminotransferase, alanine aminotransferase, bilirubin, alkaline phosphatase, and gamma-glutamyl transpeptidase) and liver histology were studied. The animals belonging to group 2 (TPVL) developed extrahepatic portosystemic collateral circulation, associated with mesenteric venous vasculopathy without hepatic destructurization or portal hypertension. Animals from group 3 (TAA) developed cirrhosis and portal hypertension but not extrahepatic portosystemic collateral circulation, or mesenteric venous vasculopathy. Finally, the animals from group 4 (TPVL + TAA) developed cirrhosis, portal hypertension, portosystemic collateral circulation, and mesenteric venous vasculopathy. The association of TPVL and TAA can be used to obtain a model of chronic portal hypertension in the rat that includes all the alterations that patients with hepatic cirrhosis usually have. This could, therefore, prove to be a useful tool to study the pathophysiological mechanisms involved in these alterations.
Collapse
Affiliation(s)
- Marta Méndez-López
- Psychobiology Department, Psychology School, University of Oviedo, Asturias, Spain
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Straub AC, Stolz DB, Ross MA, Hernández-Zavala A, Soucy NV, Klei LR, Barchowsky A. Arsenic stimulates sinusoidal endothelial cell capillarization and vessel remodeling in mouse liver. Hepatology 2007; 45:205-12. [PMID: 17187425 PMCID: PMC1764828 DOI: 10.1002/hep.21444] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
UNLABELLED Trivalent arsenic [As(III)] is a well-known environmental toxicant that causes a wide range of organ-specific diseases and cancers. In the human liver, As(III) promotes vascular remodeling, portal fibrosis, and hypertension, but the pathogenesis of these As(III)-induced vascular changes is unknown. To investigate the hypothesis that As(III) targets the hepatic endothelium to initiate pathogenic change, mice were exposed to 0 or 250 parts per billion (ppb) of As(III) in their drinking water for 5 weeks. Arsenic(III) exposure did not affect the overall health of the animals, the general structure of the liver, or hepatocyte morphology. There was no change in the total tissue arsenic levels, indicating that arsenic does not accumulate in the liver at this level of exposure. However, there was significant vascular remodeling with increased sinusoidal endothelial cell (SEC) capillarization, vascularization of the peribiliary vascular plexus (PBVP), and constriction of hepatic arterioles in As(III)-exposed mice. In addition to ultrastructural demonstration of SEC defenestration and capillarization, quantitative immunofluorescence analysis revealed increased sinusoidal PECAM-1 and laminin-1 protein expression, suggesting gain of adherens junctions and a basement membrane. Conversion of SECs to a capillarized, dedifferentiated endothelium was confirmed at the cellular level with demonstration of increased caveolin-1 expression and SEC caveolae, as well as increased membrane-bound Rac1-GTPase. CONCLUSION These data demonstrate that exposure to As(III) causes functional changes in SEC signaling for sinusoidal capillarization that may be initial events in pathogenic changes in the liver.
Collapse
Affiliation(s)
- Adam C. Straub
- From the Department of Occupational and Environmental Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA
| | - Donna B. Stolz
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA
| | - Mark A. Ross
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA
| | - Araceli Hernández-Zavala
- Center for Environmental and Molecular Biology of the Lung, University of North Carolina, Chapel Hill, NC; and
| | | | - Linda R. Klei
- From the Department of Occupational and Environmental Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA
| | - Aaron Barchowsky
- From the Department of Occupational and Environmental Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA
- Address reprint requests to: Aaron Barchowsky, Ph.D., University of Pittsburgh Graduate School of Public Health, Department of Occupational and Environmental Health, Bridgeside Point, 100 Technology Drive, Rm 332, Pittsburgh, PA 15219. E-mail: ; fax: 412-624-9361
| |
Collapse
|
|
30
|
Straub AC, Stolz DB, Vin H, Ross MA, Soucy NV, Klei LR, Barchowsky A. Low level arsenic promotes progressive inflammatory angiogenesis and liver blood vessel remodeling in mice. Toxicol Appl Pharmacol 2006; 222:327-36. [PMID: 17123562 PMCID: PMC2084367 DOI: 10.1016/j.taap.2006.10.011] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2006] [Accepted: 10/09/2006] [Indexed: 12/16/2022]
Abstract
The vascular effects of arsenic in drinking water are global health concerns contributing to human disease worldwide. Arsenic targets the endothelial cells lining blood vessels, and endothelial cell activation or dysfunction may underlie the pathogenesis of both arsenic-induced vascular diseases and arsenic-enhanced tumorigenesis. The purpose of the current studies was to demonstrate that exposing mice to drinking water containing environmentally relevant levels of arsenic promoted endothelial cell dysfunction and pathologic vascular remodeling. Increased angiogenesis, neovascularization, and inflammatory cell infiltration were observed in Matrigel plugs implanted in C57BL/6 mice following 5-week exposures to 5-500 ppb arsenic [Soucy, N.V., Mayka, D., Klei, L.R., Nemec, A.A., Bauer, J.A., Barchowsky, A., 2005. Neovascularization and angiogenic gene expression following chronic arsenic exposure in mice. Cardiovasc.Toxicol 5, 29-42]. Therefore, functional in vivo effects of arsenic on endothelial cell function and vessel remodeling in an endogenous vascular bed were investigated in the liver. Liver sinusoidal endothelial cells (LSEC) became progressively defenestrated and underwent capillarization to decrease vessel porosity following exposure to 250 ppb arsenic for 2 weeks. Sinusoidal expression of PECAM-1 and laminin-1 proteins, a hallmark of capillarization, was also increased by 2 weeks of exposure. LSEC caveolin-1 protein and caveolae expression were induced after 2 weeks of exposure indicating a compensatory change. Likewise, CD45/CD68-positive inflammatory cells did not accumulate in the livers until after LSEC porosity was decreased, indicating that inflammation is a consequence and not a cause of the arsenic-induced LSEC phenotype. The data demonstrate that the liver vasculature is an early target of pathogenic arsenic effects and that the mouse liver vasculature is a sensitive model for investigating vascular health effects of arsenic.
Collapse
Affiliation(s)
- Adam C. Straub
- Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health
| | - Donna B. Stolz
- Department of Cell Biology, University of Pittsburgh School of Medicine
| | - Harina Vin
- Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health
- Department of Cell Biology, University of Pittsburgh School of Medicine
| | - Mark A. Ross
- Department of Cell Biology, University of Pittsburgh School of Medicine
| | - Nicole V. Soucy
- Department of Pharmacology and Toxicology, Dartmouth Medical School
| | - Linda R. Klei
- Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health
| | - Aaron Barchowsky
- Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health
| |
Collapse
|
|
31
|
N/A, 李 柏. N/A. Shijie Huaren Xiaohua Zazhi 2006; 14:1621-1626. [DOI: 10.11569/wcjd.v14.i16.1621] [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] [Indexed: 02/06/2023] Open
|