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Matsubara Y, Tsuboi A, Hirata I, Sumioka A, Takasago T, Tanaka H, Yamashita K, Hiyama Y, Takigawa H, Murakami E, Tsuge M, Urabe Y, Oka S. Predictive factors of portal hypertensive enteropathy exacerbations based on long-term outcomes. BMC Gastroenterol 2024; 24:287. [PMID: 39187770 PMCID: PMC11346274 DOI: 10.1186/s12876-024-03377-7] [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: 03/06/2024] [Accepted: 08/14/2024] [Indexed: 08/28/2024] Open
Abstract
BACKGROUND Portal hypertensive enteropathy (PHE) is a small-bowel lesion observed in patients with portal hypertension. The clinical significance of endoscopic findings in PHE remains unclear. We aimed to clarify the clinical significance and predictive factors of capsule endoscopic findings in patients with PHE based on long-term outcomes. METHODS This retrospective study enrolled 55 patients with PHE (33 males and 22 females; median age, 64 years; range, 23-87) followed for > 3 years using capsule endoscopy (CE) between February 2009 and May 2023. We evaluated the clinical factors affecting PHE exacerbations and the effects of PHE exacerbations on gastrointestinal bleeding by comparing exacerbated and unchanged PHE groups. RESULTS Overall, 3 (5%) patients showed improvement, 33 (60%) remained unchanged, and 19 (35%) showed exacerbation on follow-up CE. In the exacerbated group, the rates of worsened fibrosis-4 index, exacerbated esophageal varices, and exacerbated portal hypertensive gastropathy were significantly higher than those in the unchanged group (21%, 32%, and 42% vs. 3%, 6%, and 12%, respectively; P < 0.05), and the rate of splenectomy was significantly lower in the exacerbated group than in the unchanged group (5% vs. 39%, respectively; P < 0.01). In multivariate analysis, exacerbation of esophageal varices and absence of splenectomy were significantly associated with PHE exacerbation. The rate of gastrointestinal bleeding after follow-up CE was significantly high in the exacerbated group (log-rank, P = 0.037). CONCLUSIONS Exacerbation of esophageal varices and splenectomy were significantly associated with exacerbation of PHE. Exacerbated PHE requires specific attention to prevent gastrointestinal bleeding.
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Affiliation(s)
- Yuka Matsubara
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Akiyoshi Tsuboi
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
- Department of Gastroenterology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Issei Hirata
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Akihiko Sumioka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takeshi Takasago
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hidenori Tanaka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Ken Yamashita
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuichi Hiyama
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hidehiko Takigawa
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuji Urabe
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shiro Oka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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de Haan LR, van Golen RF, Heger M. Molecular Pathways Governing the Termination of Liver Regeneration. Pharmacol Rev 2024; 76:500-558. [PMID: 38697856 DOI: 10.1124/pharmrev.123.000955] [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: 11/07/2023] [Revised: 01/24/2024] [Accepted: 02/08/2024] [Indexed: 05/05/2024] Open
Abstract
The liver has the unique capacity to regenerate, and up to 70% of the liver can be removed without detrimental consequences to the organism. Liver regeneration is a complex process involving multiple signaling networks and organs. Liver regeneration proceeds through three phases: the initiation phase, the growth phase, and the termination phase. Termination of liver regeneration occurs when the liver reaches a liver-to-body weight that is required for homeostasis, the so-called "hepatostat." The initiation and growth phases have been the subject of many studies. The molecular pathways that govern the termination phase, however, remain to be fully elucidated. This review summarizes the pathways and molecules that signal the cessation of liver regrowth after partial hepatectomy and answers the question, "What factors drive the hepatostat?" SIGNIFICANCE STATEMENT: Unraveling the pathways underlying the cessation of liver regeneration enables the identification of druggable targets that will allow us to gain pharmacological control over liver regeneration. For these purposes, it would be useful to understand why the regenerative capacity of the liver is hampered under certain pathological circumstances so as to artificially modulate the regenerative processes (e.g., by blocking the cessation pathways) to improve clinical outcomes and safeguard the patient's life.
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Affiliation(s)
- Lianne R de Haan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Rowan F van Golen
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
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Qi WL, Wen J, Wen TF, Peng W, Zhang XY, Shen JY, Li X, Li C. Prognosis after splenectomy plus pericardial devascularization vs transjugular intrahepatic portosystemic shunt for esophagogastric variceal bleeding. World J Gastrointest Surg 2023; 15:1641-1651. [PMID: 37701695 PMCID: PMC10494603 DOI: 10.4240/wjgs.v15.i8.1641] [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: 03/20/2023] [Revised: 06/04/2023] [Accepted: 06/26/2023] [Indexed: 08/25/2023] Open
Abstract
BACKGROUND Portal hypertension combined with esophagogastric variceal bleeding (EGVB) is a serious complication in patients with hepatitis B virus (HBV)-related cirrhosis in China. Splenectomy plus pericardial devascularization (SPD) and transjugular intrahepatic portosystemic shunt (TIPS) are effective treatments for EGVB. However, a comparison of the effectiveness and safety of those methods is lacking. AIM To compare the prognosis after SPD vs TIPS for acute EGVB after failure of endoscopic therapy or secondary prophylaxis of variceal rebleeding (VRB) in patients with HBV-related cirrhosis combined with portal hypertension. METHODS This retrospective cohort study included 318 patients with HBV-related cirrhosis and EGVB who underwent SPD or TIPS at West China Hospital of Sichuan University during 2009-2013. Propensity score-matched analysis (PSM), the Kaplan-Meier method, and multivariate Cox regression analysis were used to compare overall survival, VRB rate, liver function abnormality rate, and hepatocellular carcinoma (HCC) incidence between the two patient groups. RESULTS The median age was 45.0 years (n = 318; 226 (71.1%) males). During a median follow-up duration of 43.0 mo, 18 (11.1%) and 33 (21.2%) patients died in the SPD and TIPS groups, respectively. After PSM, SPD was significantly associated with better overall survival (OS) (P = 0.01), lower rates of abnormal liver function (P < 0.001), and a lower incidence of HCC (P = 0.02) than TIPS. The VRB rate did not differ significantly between the two groups (P = 0.09). CONCLUSION Compared with TIPS, SPD is associated with higher postoperative OS rates, lower rates of abnormal liver function and HCC, and better quality of survival as acute EGVB treatment after failed endoscopic therapy or as secondary prophylaxis of VRB in patients with HBV-related cirrhosis combined with portal hypertension. There is no significant between-group difference in VRB rates.
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Affiliation(s)
- Wei-Li Qi
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jun Wen
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- Section for HepatoPancreatoBiliary Surgery, Department of General Surgery, The Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University & The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu 610041, Sichuan Province, China
| | - Tian-Fu Wen
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Wei Peng
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xiao-Yun Zhang
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jun-Yi Shen
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xiao Li
- Department of Interventional Therapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100000, China
| | - Chuan Li
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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Gao TM, Zhou J, Xiang XX, Jin SJ, Qian JJ, Zhang C, Zhou BH, Tang H, Bai DS, Jiang GQ. plenectomy and azygoportal disconnection decreases the risk of hepatocellular carcinoma for cirrhosis patients with portal hypertension bleeding: a 10-year retrospective follow-up study based on the inverse probability of treatment weighting method. J Gastroenterol 2023; 58:503-512. [PMID: 36943530 DOI: 10.1007/s00535-023-01982-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 03/12/2023] [Indexed: 03/23/2023]
Abstract
BACKGROUND Liver cirrhosis is the highest risk factor for hepatocellular carcinoma (HCC) worldwide. However, etiological therapy is the only option in cirrhosis patients to decrease the HCC risk. The aim of this study was to explore whether laparoscopic splenectomy and azygoportal disconnection (LSD) decreases the risk of HCC for patients with cirrhotic portal hypertension (CPH). METHODS Between April 2012 and April 2021, we identified 595 CPH patients in our hepatobiliary pancreatic center who were diagnosed with gastroesophageal variceal bleeding and secondary hypersplenism, and performed a 10-year retrospective follow-up. Inverse probability of treatment weighting (IPTW) was used to adjust for potential confounders, weighted Kaplan-Meier curves and logistic regression to estimate survival and risk differences. RESULTS According to the method of therapy, patients were divided into LSD (n = 345) and endoscopic therapy (ET; n = 250) groups. Kaplan-Meier analysis revealed that patients who underwent LSD had higher survival benefit with those who underwent ET (P < 0.001). At the end of the follow-up, ET group was associated with a higher HCC incidence density compared with LSD group (28.1/1000 vs 9.6/1000 person-years; Rate ratio [RR] 2.922, 95% confidence intervals [CI] 1.599-5.338). In addition, logistic regression analyses weighted by IPTW revealed that, compared with ET, LSD was an independent protective predictor of HCC incidence (odds ratio [OR] 0.440, 95% CI 0.316-0.612; P < 0.001). CONCLUSIONS Considering the better postoperative survival and the ability to prevent HCC in CPH patients with gastroesophageal variceal bleeding and secondary hypersplenism, LSD is worth popularization in situations where liver donors are scarce.
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Affiliation(s)
- Tian-Ming Gao
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, 98 West Nantong Rd, Yangzhou, 225001, China
| | - Jie Zhou
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, 98 West Nantong Rd, Yangzhou, 225001, China
- Department of Hepatobiliary Surgery, The First Clinical College, Dalian Medical University, 9 West Section of South Port Arthur Rd, Dalian, 116027, Liaoning, China
| | - Xiao-Xing Xiang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, 98 West Nantong Rd, Yangzhou, 225001, China
- Department of Digestive Diseases, Clinical Medical College, Yangzhou University, 98 West Nantong Rd, Yangzhou, 225001, China
| | - Sheng-Jie Jin
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, 98 West Nantong Rd, Yangzhou, 225001, China
| | - Jian-Jun Qian
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, 98 West Nantong Rd, Yangzhou, 225001, China
| | - Chi Zhang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, 98 West Nantong Rd, Yangzhou, 225001, China
| | - Bao-Huan Zhou
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, 98 West Nantong Rd, Yangzhou, 225001, China
| | - Hua Tang
- The Administration Office, Yangzhou Blood Center, Yangzhou, 225001, China
| | - Dou-Sheng Bai
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, 98 West Nantong Rd, Yangzhou, 225001, China.
| | - Guo-Qing Jiang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, 98 West Nantong Rd, Yangzhou, 225001, China.
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Zhao Y, Zhou R, Guo Y, Chen X, Zhang A, Wang J, Ji F, Qin B, Geng J, Kong G, Li Z. Improvement of gut microbiome and intestinal permeability following splenectomy plus pericardial devascularization in hepatitis B virus-related cirrhotic portal hypertension. Front Immunol 2022; 13:941830. [PMID: 36159870 PMCID: PMC9493484 DOI: 10.3389/fimmu.2022.941830] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 08/15/2022] [Indexed: 11/17/2022] Open
Abstract
The gut microbiome is an essential component of the intestinal mucosal barrier, critical in regulating intestinal permeability. Microbiome dysbiosis and intestinal permeability changes are commonly encountered conditions in patients with cirrhosis and are closely related to its development and further complications. However, alterations in the gut microbiome and intestinal permeability in chronic hepatitis B virus (HBV) patients with cirrhotic portal hypertension after undergoing a splenectomy plus pericardial devascularization (SPD) have not been investigated. This study recruited 22 patients who were measured against themselves on the study parameters before and after an SPD, along with 20 healthy controls. Methodologically, fecal samples were collected for gut microbiome analysis by 16S ribosomal DNA sequencing, and peripheral blood samples were obtained to examine the liver function and intestinal permeability. This study showed that the community structure of the gut microbiomes in patients before the SPD exhibited obvious differences from those in the healthy control group. They also exhibited a decreased bacterial community richness, increased intestinal permeability, and enhanced inflammation compared with the healthy controls. These issues were further aggravated two weeks after the SPD. There was also evidence of significantly higher abundances of Streptococcaceae, Enterobacteriaceae, and Enterococcaceae than those in the healthy control group. However, 12 months after the surgery, 12 of the 16 patient-associated genera recovered, of which 10 reached normal levels. Additionally, the microbiome diversity increased; the bacterial composition was back to a level similar to the healthy controls. Liver function, intestinal permeability, and inflammation levels all improved compared with preoperative levels. Furthermore, correlation analyses indicated that the five recovered bacterial taxa and the Shannon diversity index were correlated with several improved clinical indicators. Altogether, the improvements in the liver function and intestinal permeability in HBV-related cirrhotic patients may be related to the restoration of the gut microbiome after an SPD.
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Affiliation(s)
- Yang Zhao
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Rui Zhou
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Ying Guo
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Xi Chen
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Aiyu Zhang
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Jiayin Wang
- School of Computer Science and Technology, Xi’an Jiaotong University, Xi’an, China
| | - Fanpu Ji
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Bowen Qin
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Jing Geng
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Guangyao Kong
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Zongfang Li
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
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Zhang S, Lu S, Li Z. Extrahepatic factors in hepatic immune regulation. Front Immunol 2022; 13:941721. [PMID: 36052075 PMCID: PMC9427192 DOI: 10.3389/fimmu.2022.941721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/28/2022] [Indexed: 11/13/2022] Open
Abstract
The liver is a site of complex immune activity. The hepatic immune system tolerates harmless immunogenic loads in homeostasis status, shelters liver function, while maintaining vigilance against possible infectious agents or tissue damage and providing immune surveillance at the same time. Activation of the hepatic immunity is initiated by a diverse repertoire of hepatic resident immune cells as well as non-hematopoietic cells, which can sense "danger signals" and trigger robust immune response. Factors that mediate the regulation of hepatic immunity are elicited not only in liver, but also in other organs, given the dual blood supply of the liver via both portal vein blood and arterial blood. Emerging evidence indicates that inter-organ crosstalk between the liver and other organs such as spleen, gut, lung, adipose tissue, and brain is involved in the pathogenesis of liver diseases. In this review, we present the features of hepatic immune regulation, with particular attention to the correlation with factors from extrahepatic organ. We describe the mechanisms by which other organs establish an immune association with the liver and then modulate the hepatic immune response. We discuss their roles and distinct mechanisms in liver homeostasis and pathological conditions from the cellular and molecular perspective, highlighting their potential for liver disease intervention. Moreover, we review the available animal models and methods for revealing the regulatory mechanisms of these extrahepatic factors. With the increasing understanding of the mechanisms by which extrahepatic factors regulate liver immunity, we believe that this will provide promising targets for liver disease therapy.
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Affiliation(s)
- Shaoying Zhang
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi International Cooperation Base for Inflammation and Immunity, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Shemin Lu
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi International Cooperation Base for Inflammation and Immunity, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, China
| | - Zongfang Li
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi International Cooperation Base for Inflammation and Immunity, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
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Fujisaki H, Fukami Y, Arikawa T, Saito T, Osawa T, Komatsu S, Kaneko K, Kurokawa T, Nonami T, Sano T. Long-term results of laparoscopic Hassab's procedure for esophagogastric varices with portal hypertension. Asian J Endosc Surg 2022; 15:505-512. [PMID: 35132809 DOI: 10.1111/ases.13038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/29/2021] [Accepted: 01/22/2022] [Indexed: 11/28/2022]
Abstract
INTRODUCTION Recent reports have shown laparoscopic gastric devascularization and splenectomy (Hassab's procedure) to be a safe and effective treatment for esophagogastric varices with portal hypertension. However, the long-term postoperative results remain unclear. METHODS Between 2009 and 2015, 17 patients with portal hypertension and esophagogastric varices underwent laparoscopic Hassab's procedure at our institution. Two patients were lost to long-term follow-up (at least 2 years) and excluded. The remaining 15 patients' data and endoscopic findings were retrospectively reviewed. RESULTS The median postoperative follow-up period was 56 months. The median spleen volume, operation time, blood loss, and length of postoperative hospital stay were 651 (320-1,265) mL, 305 (275-547) minutes, 347 (24-1,131) mL, and 20 (8-41) days, respectively. According to the endoscopic findings 1 year after surgery, the esophagogastric varices disappeared in three patients and improved in 12 patients. The median platelet count was significantly higher 1 year after surgery (19.7 × 104 /dL) than before surgery (5.5 × 104 /dL) (P < .001) and remained stable 2 years after surgery. Two patients died of liver disease. The remaining 13 patients, with a median postoperative follow-up of 57 months, were alive without bleeding from esophagogastric varices. CONCLUSION Laparoscopic Hassab's procedure is a feasible treatment for esophagogastric varices with portal hypertension in terms of both short- and long-term results.
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Affiliation(s)
- Hiroyuki Fujisaki
- Division of Gastroenterological Surgery, Department of Surgery, Aichi Medical University, Nagakute, Japan
| | - Yasuyuki Fukami
- Division of Gastroenterological Surgery, Department of Surgery, Aichi Medical University, Nagakute, Japan
| | - Takashi Arikawa
- Division of Gastroenterological Surgery, Department of Surgery, Aichi Medical University, Nagakute, Japan
| | - Takuya Saito
- Division of Gastroenterological Surgery, Department of Surgery, Aichi Medical University, Nagakute, Japan
| | - Takaaki Osawa
- Division of Gastroenterological Surgery, Department of Surgery, Aichi Medical University, Nagakute, Japan
| | - Shunichiro Komatsu
- Division of Gastroenterological Surgery, Department of Surgery, Aichi Medical University, Nagakute, Japan
| | - Kenitiro Kaneko
- Division of Gastroenterological Surgery, Department of Surgery, Aichi Medical University, Nagakute, Japan
| | - Tsuyoshi Kurokawa
- Division of Gastroenterological Surgery, Department of Surgery, Aichi Medical University, Nagakute, Japan
| | - Toshiaki Nonami
- Division of Gastroenterological Surgery, Department of Surgery, Aichi Medical University, Nagakute, Japan
| | - Tsuyoshi Sano
- Division of Gastroenterological Surgery, Department of Surgery, Aichi Medical University, Nagakute, Japan
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8
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Elchaninov A, Vishnyakova P, Sukhikh G, Fatkhudinov T. Spleen: Reparative Regeneration and Influence on Liver. Life (Basel) 2022; 12:626. [PMID: 35629294 PMCID: PMC9148119 DOI: 10.3390/life12050626] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 04/14/2022] [Accepted: 04/21/2022] [Indexed: 02/06/2023] Open
Abstract
This review considers experimental findings on splenic repair, obtained in two types of small animal (mouse, rat, and rabbit) models: splenic resections and autologous transplantations of splenic tissue. Resection experiments indicate that the spleen is able to regenerate, though not necessarily to the initial volume. The recovery lasts one month and preserves the architecture, albeit with an increase in the relative volume of lymphoid follicles. The renovated tissues, however, exhibit skewed functional profiles; notably, the decreased production of antibodies and the low cytotoxic activity of T cells, consistent with the decline of T-dependent zones and prolonged reduction in T cell numbers. Species-specific differences are evident as well, with the post-repair organ mass deficiency most pronounced in rabbit models. Autotransplantations of splenic material are of particular clinical interest, as the procedure can possibly mitigate the development of post-splenectomy syndrome. Under these conditions, regeneration lasts 1-2 months, depending on the species. The transplants effectively destroy senescent erythrocytes, assist in microbial clearance, and produce antibodies, thus averting sepsis and bacterial pneumonia. Meanwhile, cellular sources of splenic recovery in such models remain obscure, as well as the time required for T and B cell number reconstitution.
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Affiliation(s)
- Andrey Elchaninov
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia; (P.V.); (G.S.)
- Histology Department, Medical Institute, Peoples’ Friendship University of Russia, 117198 Moscow, Russia;
| | - Polina Vishnyakova
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia; (P.V.); (G.S.)
- Histology Department, Medical Institute, Peoples’ Friendship University of Russia, 117198 Moscow, Russia;
| | - Gennady Sukhikh
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia; (P.V.); (G.S.)
| | - Timur Fatkhudinov
- Histology Department, Medical Institute, Peoples’ Friendship University of Russia, 117198 Moscow, Russia;
- Laboratory of Growth and Development, Scientific Research Institute of Human Morphology, 117418 Moscow, Russia
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9
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Asnaashari S, Amjad E, Sokouti B. A comprehensive investigation on liver regeneration: a meta-analysis and systems biology approach. Clin Exp Hepatol 2021; 7:183-190. [PMID: 34295986 PMCID: PMC8284170 DOI: 10.5114/ceh.2021.107564] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 02/14/2021] [Indexed: 12/15/2022] Open
Abstract
AIM OF THE STUDY Liver regeneration is one of the essential fields of regenerative medicine as a branch of tissue engineering and molecular biology that draws global researchers' attention. This study aims to conduct a systematic review and meta-analysis on the high-throughput gene expression microarray dataset of liver regeneration on the NCBI-GEO database to identify the significant genes and signaling pathways and confirm the genes from literature studies on associated diseases. MATERIAL AND METHODS We thoroughly searched the NCBI-GEO database to retrieve and screen the GEO microarray datasets' contents. Due to the inclusion of different species in eligible GEO datasets in the meta-analysis, the list of significant genes for the random-effects model were identified. Moreover, we carried out detailed gene analyses for three main gene ontology components and the KEGG signaling pathway. Furthermore, we investigated the possibility of genes' association with liver cancer through the Kaplan-Meier plot. RESULTS The random-effects model from six eligible GEO datasets identified 71 genes with eight down-regulated and 63 up-regulated genes. The target genes are involved in various cellular functions such as cell proliferation, cell death, and cell cycle control. Finally, we noted that 58 out of 71 genes are associated with different types of diseases related explicitly to other liver and inflammation diseases. CONCLUSIONS The current study assessed various GEO datasets at the early stages of liver regeneration with promising results. The present systematic review and meta-analysis results are beneficial for future novel drug design and discovery specifically for patients in the liver transplantation process.
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Affiliation(s)
| | | | - Babak Sokouti
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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10
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Kanou S, Miyashita T, Yamamoto Y, Takada S, Nakura M, Okazaki M, Ohbatake Y, Nakanuma S, Makino I, Tajima H, Takamura H, Fushida S, Ohta T. Prophylactic Effect of Recombinant Human Soluble Thrombomodulin for Hepatic Sinusoidal Obstruction Syndrome Model Mice. In Vivo 2021; 34:1037-1045. [PMID: 32354890 DOI: 10.21873/invivo.11873] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 03/17/2020] [Accepted: 03/18/2020] [Indexed: 02/08/2023]
Abstract
AIM The present study aimed to examine the effects of prophylactic administration of recombinant human soluble thrombomodulin (rTM) for the prevention of sinusoidal obstruction syndrome (SOS). MATERIALS AND METHODS Crl:CD1 mice were allocated to the rTM, placebo, and control groups. The rTM group received an intraperitoneal administration of rTM, with intraperitoneal administration of monocrotaline (MCT) 1 h later. The placebo group received PBS instead of rTM, and the control group received PBS instead of rTM and MCT. Mice were sacrificed 48 h after MCT administration, and blood and liver tissues were evaluated. Immunostaining was performed using anti-CD42b and anti-SE-1 antibodies, and AZAN staining. Levels of plasminogen activator inhibitor (PAI-1) and endothelial nitric oxide synthase (eNOS) in whole liver tissues were estimated using RT-PCR. RESULTS Hematoxylin-eosin staining showed that SOS-related findings were markedly attenuated in the rTM group compared to the placebo group. CD42b immunostaining showed the presence of extravasated platelet activation (EPA) in the Disse space in the placebo group, but this was less noticeable in the rTM group. PAI-1 levels were significantly lower in the rTM group than in the placebo group in RT-PCR. However, eNOS levels were significantly higher in the rTM group than in the placebo group. CONCLUSION Administration of rTM may prevent SOS by protecting sinusoidal endothelial cells.
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Affiliation(s)
- Shunsuke Kanou
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Tomoharu Miyashita
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Yasuhiko Yamamoto
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Satoshi Takada
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Makoto Nakura
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Mitsuyoshi Okazaki
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Yoshinao Ohbatake
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Shinichi Nakanuma
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Isamu Makino
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Hidehiro Tajima
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Hiroyuki Takamura
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Sachio Fushida
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Tetsuo Ohta
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
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11
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Konishi T, Yoshidome H, Shimizu H, Yoshitomi H, Furukawa K, Takayashiki T, Kuboki S, Takano S, Miyazaki M, Ohtsuka M. Splenic enlargement induced by preoperative chemotherapy is a useful indicator for predicting liver regeneration after resection for colorectal liver metastases. World J Surg Oncol 2020; 18:139. [PMID: 32576191 PMCID: PMC7313099 DOI: 10.1186/s12957-020-01918-4] [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: 01/31/2020] [Accepted: 06/15/2020] [Indexed: 11/13/2022] Open
Abstract
Background Conversion chemotherapy may downsize unresectable colorectal liver metastases (CRLMs), but may cause liver injury and splenic enlargement. The effect of preoperative chemotherapy on liver regeneration after liver resection remains undetermined. The aim of this study was to examine whether splenic enlargement induced by preoperative chemotherapy is an indicator to identify high-risk patients for impaired liver regeneration and liver dysfunction after resection. Methods We retrospectively reviewed 118 Japanese patients with CRLMs. Fifty-one patients had conversion chemotherapy. The other 67 patients underwent up-front liver resection. We clarified effects of conversion chemotherapy on splenic volume, liver function, and postoperative liver regeneration. Perioperative outcome was also analyzed. Results A ratio of the splenic volume before and after chemotherapy (SP index) in the oxaliplatin-based chemotherapy group was significantly greater than other chemotherapy groups after 9 or more chemotherapy cycles. Patients whose SP index was 1.2 or more had significantly higher indocyanine green retention rate at 15 min (ICG-R15) than patients without chemotherapy. Analyses of covariance showed liver regeneration rate after resection was decreased in patients whose SP index was 1.2 or more. The incidence of postoperative liver dysfunction in patients whose SP index was 1.2 or more was significantly greater than patients without chemotherapy. Multivariate analysis showed SP index was a significant predictive factor of impaired liver regeneration. Conclusions Splenic enlargement induced by preoperative chemotherapy was a useful indicator for impaired liver regeneration after resection and a decision-making tool of treatment strategy for unresectable CRLMs.
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Affiliation(s)
- Takanori Konishi
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Hiroyuki Yoshidome
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan. .,Department of Surgery, Oami Municipal Hospital, 884-1 Tomida, Oami-Shirasato-shi, Chiba, 299-3221, Japan.
| | - Hiroaki Shimizu
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Hideyuki Yoshitomi
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Katsunori Furukawa
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Tsukasa Takayashiki
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Satoshi Kuboki
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Shigetsugu Takano
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Masaru Miyazaki
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan.,Surgery and Digestive Disease Center, International University of Health and Welfare, Mita Hospital, 1-4-3 Mita, Minato-Ku, Tokyo, 108-8329, Japan
| | - Masayuki Ohtsuka
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
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12
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Elchaninov AV, Fatkhudinov TK, Vishnyakova PA, Nikitina MP, Lokhonina AV, Makarov AV, Arutyunyan IV, Kananykhina EY, Poltavets AS, Butov KR, Baranov II, Goldshtein DV, Bolshakova GB, Glinkina VV, Sukhikh GT. Molecular mechanisms of splenectomy-induced hepatocyte proliferation. PLoS One 2020; 15:e0233767. [PMID: 32531779 PMCID: PMC7292681 DOI: 10.1371/journal.pone.0233767] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 05/12/2020] [Indexed: 02/07/2023] Open
Abstract
Functional and anatomical connection between the liver and the spleen is most clearly manifested in various pathological conditions of the liver (cirrhosis, hepatitis). The mechanisms of the interaction between the two organs are still poorly understood, as there have been practically no studies on the influence exerted by the spleen on the normal liver. Mature male Sprague-Dawley rats of 250-260 g body weight, 3 months old, were splenectomized. The highest numbers of Ki67+ hepatocytes in the liver of splenectomized rats were observed at 24 h after the surgery, simultaneously with the highest index of Ki67-positive hepatocytes. After surgical removal of the spleen, expression of certain genes in the liver tissues increased. A number of genes were upregulated in the liver at a single time point of 24 h, including Ccne1, Egf, Tnfa, Il6, Hgf, Met, Tgfb1r2 and Nos2. The expression of Ccnd1, Tgfb1, Tgfb1r1 and Il10 in the liver was upregulated over the course of 3 days after splenectomy. Monitoring of the liver macrophage populations in splenectomized animals revealed a statistically significant increase in the proportion of CD68-positive cells in the liver (as compared with sham-operated controls) detectable at 24 h and 48 h after the surgery. The difference in the liver content of CD68-positive cells between splenectomized and sham-operated animals evened out by day 3 after the surgery. No alterations in the liver content of CD163-positive cells were observed in the experiments. A decrease in the proportion of CD206-positive liver macrophages was observed at 48 h after splenectomy. The splenectomy-induced hepatocyte proliferation is described by us for the first time. Mechanistically, the effect is apparently induced by the removal of spleen as a major source of Tgfb1 (hepatocyte growth inhibitor) and subsequently supported by activation of proliferation factor-encoding genes in the liver.
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Affiliation(s)
- Andrey V. Elchaninov
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I.Kulakov of Ministry of Healthcare of Russian Federation, Moscow, Russian Federation
- Histology Department, Peoples Friendship University of Russia (RUDN University), Moscow, Russian Federation
| | - Timur Kh. Fatkhudinov
- Histology Department, Peoples Friendship University of Russia (RUDN University), Moscow, Russian Federation
- Laboratory of Growth and Development, Research Institute of Human Morphology, Moscow, Russian Federation
| | - Polina A. Vishnyakova
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I.Kulakov of Ministry of Healthcare of Russian Federation, Moscow, Russian Federation
| | - Maria P. Nikitina
- Laboratory of Growth and Development, Research Institute of Human Morphology, Moscow, Russian Federation
| | - Anastasiya V. Lokhonina
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I.Kulakov of Ministry of Healthcare of Russian Federation, Moscow, Russian Federation
| | - Andrey V. Makarov
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I.Kulakov of Ministry of Healthcare of Russian Federation, Moscow, Russian Federation
- Histology Department, Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, Moscow, Russian Federation
| | - Irina V. Arutyunyan
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I.Kulakov of Ministry of Healthcare of Russian Federation, Moscow, Russian Federation
| | - Evgeniya Y. Kananykhina
- Laboratory of Growth and Development, Research Institute of Human Morphology, Moscow, Russian Federation
| | - Anastasiya S. Poltavets
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I.Kulakov of Ministry of Healthcare of Russian Federation, Moscow, Russian Federation
| | - Kirill R. Butov
- Histology Department, Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, Moscow, Russian Federation
| | - Igor I. Baranov
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I.Kulakov of Ministry of Healthcare of Russian Federation, Moscow, Russian Federation
| | - Dmitry V. Goldshtein
- Laboratory of Stem Cells Genetics, Research Center of Medical Genetics, Moscow, Russian Federation
| | - Galina B. Bolshakova
- Laboratory of Growth and Development, Research Institute of Human Morphology, Moscow, Russian Federation
| | - Valeria V. Glinkina
- Histology Department, Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, Moscow, Russian Federation
| | - Gennady T. Sukhikh
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I.Kulakov of Ministry of Healthcare of Russian Federation, Moscow, Russian Federation
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13
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Effects of laparoscopic splenectomy and azygoportal disconnection on liver synthesis function and cirrhosis: a 2-year prospective study. Surg Endosc 2019; 34:5074-5082. [PMID: 31820157 DOI: 10.1007/s00464-019-07307-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Accepted: 11/28/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND Laparoscopic splenectomy and azygoportal disconnection (LSD) is widely used for the treatment of esophagogastric variceal haemorrhage and hypersplenism owing to cirrhotic portal hypertension. However, whether LSD improves liver synthesis function and cirrhosis remains unclear. The aim of this study is to investigate the effect of LSD on liver synthesis function and cirrhosis based on a prospective 2-year follow-up study. METHODS A total of 118 patients with cirrhotic portal hypertension who underwent LSD were included in this study. We analysed clinical data including routine blood parameters, liver function, liver-synthesised proteins (antithrombin III, protein S, and protein C), liver fibrotic markers (type IV collagen (IV-C), procollagen type III (PC-III), laminin, and hyaluronidase), portal vein diameter, and portal blood flow velocity. RESULTS Postoperative portal vein diameter and portal blood flow velocity all showed gradual declines during the 2-year follow-up; compared with preoperative values, these were all significantly decreased from postoperative week (POW) 1 (all P < 0.001). Postoperative Child-Pugh scores and total bilirubin, albumin, international normalised ratio, antithrombin III, protein S, protein C, IV-C, PC-III, laminin, and hyaluronidase levels also all showed gradual improvements during the 2-year follow-up; compared with preoperative levels, these were all significantly improved from postoperative month (POM) 6, POW 1, POM 3, POM 3, POM 3, POM 6, POM 18, POW 1, POM 3, POM 24, and POM 18, respectively (all P < 0.05). CONCLUSION LSD not only decreases portal hypertension and improves liver function, it also enhances liver synthesis function and reduces liver fibrosis.
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14
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Ozaki M. Cellular and molecular mechanisms of liver regeneration: Proliferation, growth, death and protection of hepatocytes. Semin Cell Dev Biol 2019; 100:62-73. [PMID: 31669133 DOI: 10.1016/j.semcdb.2019.10.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/09/2019] [Accepted: 10/14/2019] [Indexed: 01/08/2023]
Abstract
Liver regeneration is an important and necessary process that the liver depends on for recovery from injury. The regeneration process consists of a complex network of cells and organs, including liver cells (parenchymal and non-parenchymal cells) and extrahepatic organs (thyroid, adrenal glands, pancreas, duodenum, spleen, and autonomic nervous system). The regeneration process of a normal, healthy liver depends mainly on hepatocyte proliferation, growth, and programmed cell death. Cell proliferation and growth are regulated in a cooperative manner by interleukin (IL)-6/janus kinase (Jak)/signal transducers and activators of transcription-3 (STAT3), and phosphoinositide 3-kinase (PI3-K)/phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathways. The IL-6/Jak/STAT3 pathway regulates hepatocyte proliferation and protects against cell death and oxidative stress. The PI3-K/PDK1/Akt pathway is primarily responsible for the regulation of cell size, sending mitotic signals in addition to pro-survival, antiapoptotic and antioxidative signals. Though programmed cell death may interfere with liver regeneration in a pathological situation, it seems to play an important role during the termination phase, even in a normal, healthy liver regeneration. However, further study is needed to fully elucidate the mechanisms regulating the processes of liver regeneration with regard to cell-to-cell and organ-to-organ networks at the molecular and cellular levels.
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Affiliation(s)
- Michitaka Ozaki
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University, N12, W5, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan.
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15
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Matsuda A, Kuriyama N, Mizuno S, Usui M, Sakurai H, Isaji S. Dual Effects of Large Spleen Volume After Splenectomy for the Patients With Chronic Liver Disease. Int Surg 2019; 104:412-422. [DOI: 10.9738/intsurg-d-18-00029.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Background
After splenectomy in patients with chronic liver disease, a large spleen was reported to be not only a risk factor of portal/splenic vein thrombosis (PSVT), but also a prediction for favorable improvement of liver function. This study aimed to evaluate the risk of PSVT and the improvement of liver function after splenectomy, with special attention to spleen volume (SV).
Methods
This studied included 50 patients who underwent splenectomy with diagnosed chronic liver disease between January 2005 and December 2017. After evaluation of risk factors for PSVT the cut-off value of SV for predicting PSVT was determined. According to the cut-off value of SV, 50 patients were divided into 2 groups: small-volume group (SVG) and large-volume group (LVG). Postoperative liver functions were compared between the 2 groups.
Results
Twenty-eight patients developed PSVT. Larger SV was the most significant independent risk factor for PSVT. The cut-off value of SV was 520 mL. Preoperatively, LVG had significantly higher total bilirubin, and MELD (model for end-stage liver disease) score, and had significantly higher rates of pancytopenia than SVG. Postoperatively, compared to SVG, platelet count, choline esterase, and total cholesterol in LVG were significantly increased.
Conclusion
After splenectomy in the patients with chronic liver disease, large SV is an independent risk factor for PSVT, with a clear benefit in improving liver function, if PSVT is properly diagnosed and managed.
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Affiliation(s)
- Akitoshi Matsuda
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
- Present affiliation: Department of Surgery, Mie Chuo Medical Center Hospital, Mie, Japan
| | - Naohisa Kuriyama
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Shugo Mizuno
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Masanobu Usui
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Hiroyuki Sakurai
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Shuji Isaji
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
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16
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Dar WA, Sullivan E, Bynon JS, Eltzschig H, Ju C. Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms. Liver Int 2019; 39:788-801. [PMID: 30843314 PMCID: PMC6483869 DOI: 10.1111/liv.14091] [Citation(s) in RCA: 256] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 02/13/2019] [Accepted: 02/22/2019] [Indexed: 12/11/2022]
Abstract
Liver disease causing end organ failure is a growing cause of mortality. In most cases, the only therapy is liver transplantation. However, liver transplantation is a complex undertaking and its success is dependent on a number of factors. In particular, liver transplantation is subject to the risks of ischaemia-reperfusion injury (IRI). Liver IRI has significant effects on the function of a liver after transplantation. The cellular and molecular mechanisms governing IRI in liver transplantation are numerous. They involve multiple cells types such as liver sinusoidal endothelial cells, hepatocytes, Kupffer cells, neutrophils and platelets acting via an interconnected network of molecular pathways such as activation of toll-like receptor signalling, alterations in micro-RNA expression, production of ROS, regulation of autophagy and activation of hypoxia-inducible factors. Interestingly, the cellular and molecular events in liver IRI can be correlated with clinical risk factors for IRI in liver transplantation such as donor organ steatosis, ischaemic times, donor age, and donor and recipient coagulopathy. Thus, understanding the relationship of the clinical risk factors for liver IRI to the cellular and molecular mechanisms that govern it is critical to higher levels of success after liver transplantation. This in turn will help in the discovery of therapeutics for IRI in liver transplantation - a process that will lead to improved outcomes for patients suffering from end-stage liver disease.
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Affiliation(s)
- Wasim A. Dar
- Department of Surgery, McGovern Medical School at UT Health, Houston, TX
| | - Elise Sullivan
- Department of Anesthesia, McGovern Medical School at UT Health, Houston, TX
| | - John S. Bynon
- Department of Surgery, McGovern Medical School at UT Health, Houston, TX
| | - Holger Eltzschig
- Department of Anesthesia, McGovern Medical School at UT Health, Houston, TX
| | - Cynthia Ju
- Department of Anesthesia, McGovern Medical School at UT Health, Houston, TX
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17
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Huang N, Ji F, Zhang S, Pu Y, Jiang A, Zhou R, Ji Y, Wei W, Yang J, Li Z. Effect of Splenectomy on Serum Cytokine Profiles in Hepatitis B Virus-Related Cirrhosis Patients with Portal Hypertension. Viral Immunol 2018; 31:371-378. [PMID: 29565232 DOI: 10.1089/vim.2017.0176] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Emerging evidences showed the promoting role of spleen in the development of cirrhosis and hepatocellular carcinoma, in the context of portal hypertension and hypersplenism due to hepatitis B virus-related cirrhosis. In this study, we tried to explore the precise mechanism of how spleen regulates this process from the serum cytokines profile level. Compared with the 16 healthy subjects, the RayBio Human Cytokine Antibody Array identified 136 cytokines differentially expressed in 36 cirrhotic patients. Splenectomy resulted in significant changes in 28 cytokines. Differentially expressed cytokines were mainly involved in cellular processes, responses to stimuli, immune processes, binding, extracellular regions, and extracellular matrix. These cytokines were mainly enriched in cytokine-cytokine receptor interactions, Jak-STAT and MAPK signaling pathways, and pathways in cancer. These results may provide new clues to the function of the spleen, and modulation of cytokine expression maybe a potential alternative therapeutic strategy for these patients.
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Affiliation(s)
- Na Huang
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 2 Shaanxi Provincial Engineering Research Center of Biotherapy & Translational Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
| | - Fanpu Ji
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 3 Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
| | - Shu Zhang
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 3 Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
| | - Yansong Pu
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 3 Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
| | - An Jiang
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 3 Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
| | - Rui Zhou
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 3 Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
| | - Yuanyuan Ji
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
| | - Wei Wei
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
| | - Jun Yang
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 2 Shaanxi Provincial Engineering Research Center of Biotherapy & Translational Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
| | - Zongfang Li
- 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 2 Shaanxi Provincial Engineering Research Center of Biotherapy & Translational Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 3 Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an, People's Republic of China
- 4 Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University , Xi'an, People's Republic of China
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18
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Liu Y, Li J, Jin Y, Zhao L, Zhao F, Feng J, Li A, Wei Y. Splenectomy Leads to Amelioration of Altered Gut Microbiota and Metabolome in Liver Cirrhosis Patients. Front Microbiol 2018; 9:963. [PMID: 29867867 PMCID: PMC5962811 DOI: 10.3389/fmicb.2018.00963] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 04/24/2018] [Indexed: 12/12/2022] Open
Abstract
Dysbiosis of gut microbiota and metabolome is a frequently encountered condition in liver cirrhosis (LC) patients. The severity of liver dysfunction was found to be correlated with the degree of microbial dysbiosis. Several clinical studies have indicated liver function improvement after therapeutic splenectomy for LC-induced hypersplenism. We sought to determine whether such post-splenectomy outcome is pertinent to modulation of the abnormal gut microenvironment in LC patients. A cross-sectional study including 12 LC patients and 16 healthy volunteers was first conducted, then a before-after study in the cohort of patients was carried out before and 6 months after splenectomy. Fecal samples were collected in hospital. Temporal bacterial (n = 40) and metabolomics (n = 30) profiling was performed using 16s rRNA gene sequencing and ultra performance liquid chromatography/mass spectrometer (UPLC/MS), respectively. Our results revealed that microbial composition in patients was clearly different from that in healthy controls (HCs), evidenced by considerable taxonomic variation. Along with improved liver function (Child-Pugh score), the patients also displayed similar gut microbiota profile and predicted metagenome function to that of HCs after splenectomy. Enterobacteriaceae and Streptococcaceae, two LC-enriched families showing positive relation with Child-Pugh score, exhibited significantly decreased abundance after splenectomy. At the genus level, 11 genera were differentially abundant between patients and HCs, but 9 genera of them restituted to normal levels by certain degree after splenectomy. PICRUSt analysis showed that the relative abundance of 17 KEGG pathways was partially restored after splenectomy. Four of them were amino acid-related pathways: lysine degradation, tryptophan degradation, amino acid metabolism, and protein digestion and absorption. These findings were supported by metabonomics results which showed that relative abundance of amino acid and corresponding catabolites changed toward normal. In addition to the variations in the relative abundances of bacteria and metabolites, the correlation between them also altered in patients after splenectomy. Dysbiosis in gut microbiome and related metabolism of LC patients was partially corrected after splenectomy. Whether the improved gut microenvironment could prevent LC-related complications and delay the progress of LC is a propitious objective for future study. TRIAL REGISTRATION ChiCTR-OOB-15007409. Registered November 15, 2015.
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Affiliation(s)
| | | | | | | | | | | | | | - Yunwei Wei
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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19
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Zhang X, Li C, Wen T, Peng W, Yan L, Li B, Yang J, Wang W, Xu M, Zeng Y. Synchronous splenectomy and hepatectomy for patients with small hepatocellular carcinoma and pathological spleen: neutrophil to lymphocyte ratio changes can predict the prognosis. Oncotarget 2018; 8:46298-46311. [PMID: 28549349 PMCID: PMC5542268 DOI: 10.18632/oncotarget.17758] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 03/17/2017] [Indexed: 02/05/2023] Open
Abstract
Background Treatments about small hepatocellular carcinoma (HCC) and hypersplenism associated with good hepatic reserve are not well established. The aim of this study was to investigate the outcome of synchronous hepatectomy and splenectomy for those patients. Study Design Splenomegaly and hypersplenism were defined as a pathological spleen. Seven hundred fifty-six patients with small HCC (381 with a pathological spleen, 375 without a pathological spleen) were divided into three groups. One hundred ten of 381 patients underwent synchronous hepatectomy and splenectomy (group A), 271 of 381 patients underwent hepatectomy alone (Group B) and 375 patients without pathological spleen underwent hepatectomy alone (Group C). The influence of pathological spleen, outcome of different treatments and systemic inflammatory response indexes were analyzed. Results Both overall survival (OS, P=0.023) and disease-free survival (DFS, P=0.020) were significantly increased in group C compared to group B. A pathological spleen was a significant independent prognostic factor for OS and DFS among those two groups. In addition, OS (P=0.025) and DFS (P=0.004) were increased in the group A compared to group B. Splenectomy and neutrophil to lymphocyte ratio changes (ΔNLR) were significant independent prognostic factors of the prognosis for patients in groups A and B. Conclusions A Pathological spleen influences the outcome of HCC patients. Synchronous hepatectomy and splenectomy should be performed among patients with small HCC and a pathological spleen. ΔNLR can predict the prognosis of these patients.
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Affiliation(s)
- Xiaoyun Zhang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Chuan Li
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Tianfu Wen
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Wei Peng
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lunan Yan
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Bo Li
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jiayin Yang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Wentao Wang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Mingqing Xu
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yong Zeng
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
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20
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Takahashi Y, Matsuura T, Yoshimaru K, Yanagi Y, Hayashida M, Taguchi T. Liver graft-to-spleen volume ratio as a useful predictive factor of the early graft function in children and young adults transplanted for biliary atresia: a retrospective study. Transpl Int 2018; 31:620-628. [PMID: 29424478 DOI: 10.1111/tri.13131] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 10/10/2017] [Accepted: 01/30/2018] [Indexed: 01/10/2023]
Abstract
A graft volume/standard liver volume ratio (GV/SLV) > 35% or graft/recipient weight ratio (GRWR) > 0.8% has been considered as a standard criteria of graft selection. Even if the graft size meets these selection criteria, small-for-size syndrome can still occur depending on the portal venous flow (PVF). The aim of this study was to identify other factors contributing to portal hyperperfusion and the post-transplant course, focusing on the graft volume-to-spleen volume ratio (GV/SV). Thirty-seven BA patients who underwent living donor liver transplantation were reviewed retrospectively. First, we evaluated the preoperative factors contributing to portal hyperperfusion. Second, we evaluated the factors contributing to post-transplant complications, such as thrombocytopenia, hyperbilirubinemia, and coagulopathy. The GV/SLV was >35% in all cases; however, portal hyperperfusion (≥250 ml/min/100 g graft) was found in 12 recipients (35.3%). Furthermore, although the GRWR was >0.8% in over 90% of cases, portal hyperperfusion was found in 10 recipients (32.3%). In contrast, the GV/SV showed a significant correlation with the PVF after reperfusion. If the GV/SV was <0.88, about 80% of recipients developed portal hyperperfusion. Furthermore, the GV/SV also showed a significant correlation with post-transplant persistent thrombocytopenia and hyperbilirubinemia. The GV/SV < 0.88 predicts portal hyperperfusion, post-transplant persistent thrombocytopenia, and hyperbilirubinemia.
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Affiliation(s)
- Yoshiaki Takahashi
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Maidashi, Fukuoka, Japan
| | - Toshiharu Matsuura
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Maidashi, Fukuoka, Japan
| | - Koichiro Yoshimaru
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Maidashi, Fukuoka, Japan
| | - Yusuke Yanagi
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Maidashi, Fukuoka, Japan
| | - Makoto Hayashida
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Maidashi, Fukuoka, Japan
| | - Tomoaki Taguchi
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Maidashi, Fukuoka, Japan
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21
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Liu G, Xie C, Fang Y, Qian K, Liu Q, Liu G, Cao Z, Du H, Fu J, Xu X. Splenectomy after partial hepatectomy accelerates liver regeneration in mice by promoting tight junction formation via polarity protein Par 3-aPKC. Life Sci 2017; 192:91-98. [PMID: 29166570 DOI: 10.1016/j.lfs.2017.11.032] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 10/28/2017] [Accepted: 11/18/2017] [Indexed: 12/26/2022]
Abstract
AIMS Several experimental studies have demonstrated that removal of the spleen accelerates liver regeneration after partial hepatectomy. While the mechanism of splenectomy promotes liver regeneration by the improvement of the formation of tight junction and the establishment of hepatocyte polarity is still unknown. MAIN METHODS We analyzed the cytokines, genes and proteins expression between 70% partial hepatectomy mice (PHx) and simultaneous 70% partial hepatectomy and splenectomy mice (PHs) at predetermined timed points. KEY FINDINGS Compared with the PHx group mice, splenectomy accelerated hepatocyte proliferation in PHs group. The expression of Zonula occludens-1 (ZO-1) indicated that splenectomy promotes the formation of tight junction during liver regeneration. TNF-α, IL-6, HGF, TSP-1 and TGF-β1 were essential factors for the formation of tight junction and the establishment of hepatocytes polarity in liver regeneration. After splenectomy, Partitioning defective 3 homolog (Par 3) and atypical protein kinase C (aPKC) regulate hepatocyte localization and junctional structures in regeneration liver. SIGNIFICANCE Our data suggest that the time course expression of TNF-α, IL-6, HGF, TSP-1, and TGF-β1 and the change of platelets take part in liver regeneration. Combination with splenectomy accelerates liver regeneration by improvement of the tight junction formation which may help to establish hepatocyte polarity via Par 3-aPKC. This may provide a clue for us that splenectomy could accelerate liver regeneration after partial hepatectomy of hepatocellular carcinoma and living donor liver transplantation.
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Affiliation(s)
- Guoxing Liu
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Chengzhi Xie
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Yu Fang
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Ke Qian
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Qiang Liu
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Gao Liu
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Zhenyu Cao
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Huihui Du
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Jie Fu
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Xundi Xu
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
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22
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Tao Y, Wang M, Chen E, Tang H. Liver Regeneration: Analysis of the Main Relevant Signaling Molecules. Mediators Inflamm 2017; 2017:4256352. [PMID: 28947857 PMCID: PMC5602614 DOI: 10.1155/2017/4256352] [Citation(s) in RCA: 126] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 07/19/2017] [Accepted: 08/10/2017] [Indexed: 02/06/2023] Open
Abstract
Liver regeneration is a highly organized tissue regrowth process and is the most important reaction of the liver to injury. The overall process of liver regeneration includes three phases: priming stage, proliferative phase, and termination phase. The initial step aims to induce hepatocytes to be sensitive to growth factors with the aid of some cytokines, including TNF-α and IL-6. The proliferation phase promotes hepatocytes to re-enter G1 with the stimulation of growth factors. While during the termination stage, hepatocytes will discontinue to proliferate to maintain normal liver mass and function. Except for cytokine- and growth factor-mediated pathways involved in regulating liver regeneration, new substances and technologies emerge to influence the regenerative process. Here, we reviewed novel and important signaling molecules involved in the process of liver regeneration to provide a cue for further research.
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Affiliation(s)
- Yachao Tao
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Menglan Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Enqiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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23
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Li L, Duan M, Chen W, Jiang A, Li X, Yang J, Li Z. The spleen in liver cirrhosis: revisiting an old enemy with novel targets. J Transl Med 2017; 15:111. [PMID: 28535799 PMCID: PMC5442653 DOI: 10.1186/s12967-017-1214-8] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 05/16/2017] [Indexed: 12/15/2022] Open
Abstract
The spleen is a secondary lymphoid organ which can influence the progression of multiple diseases, notably liver cirrhosis. In chronic liver diseases, splenomegaly and hypersplenism can manifest following the development of portal hypertension. These splenic abnormalities correlate with and have been postulated to facilitate the progression of liver fibrosis to cirrhosis, although precise mechanisms remain poorly understood. In this review, we summarize the literature to highlight the mechanistic contributions of splenomegaly and hypersplenism to the development of liver cirrhosis, focusing on three key aspects: hepatic fibrogenesis, hepatic immune microenvironment dysregulation and liver regeneration. We conclude with a discussion of the possible therapeutic strategies for modulating splenic abnormalities, including the novel potential usage of nanomedicine in non-surgically targetting splenic disorders for the treatment of liver cirrhosis.
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Affiliation(s)
- Liang Li
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China.,Liver and Spleen Diseases Research Center, Shaanxi Province, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China
| | - Mubing Duan
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Bundoora, VIC, Australia
| | - Weisan Chen
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China.,Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Bundoora, VIC, Australia
| | - An Jiang
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China.,Liver and Spleen Diseases Research Center, Shaanxi Province, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China.,Department of General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China
| | - Xiaoming Li
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China
| | - Jun Yang
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China. .,Liver and Spleen Diseases Research Center, Shaanxi Province, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China. .,Department of Pathology, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China.
| | - Zongfang Li
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China. .,Liver and Spleen Diseases Research Center, Shaanxi Province, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China.
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24
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Takahashi Y, Matsuura T, Yanagi Y, Yoshimaru K, Taguchi T. The role of splenectomy before liver transplantation in biliary atresia patients. J Pediatr Surg 2016; 51:2095-2098. [PMID: 27720430 DOI: 10.1016/j.jpedsurg.2016.09.048] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 09/12/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND/PURPOSE There is currently no unified view regarding whether liver transplantation or splenectomy should be performed for hypersplenism before liver transplantation in biliary atresia (BA) patients. We herein describe the efficacy of splenectomy before liver transplantation. METHODS Splenectomy was performed in ten patients with hypersplenism associated with BA. We retrospectively reviewed their perioperative and postoperative courses, the number of leukocytes and thrombocytes, and the MELD score. RESULTS The mean age was 17.5±7.0years (range 11-31years), and the male-to-female ratio was 1:1. The platelet and leukocyte levels increased after splenectomy and returned to normal levels one month postoperatively. The mean MELD score after splenectomy was significantly decreased after splenectomy: 10±2.1 vs 7.6±1.8. In particular, PT-INR improved. Five patients underwent liver transplantation because of hepatopulmonary syndrome and repeated bouts of cholangitis, whereas the remaining five patients did not undergo liver transplantation because of improvements in the liver function (the mean follow-up period was 56months). The postoperative complications included portal vein thrombosis and intestinal perforation, but the patient survival rates remained at 100%. CONCLUSION After splenectomy, both pancytopenia and the liver function clearly improved. Splenectomy should therefore be a treatment option for patients with hypersplenism before liver transplantation. LEVEL OF EVIDENCE Retrospective Comparative Study - Level III.
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Affiliation(s)
- Yoshiaki Takahashi
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
| | - Toshiharu Matsuura
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
| | - Yusuke Yanagi
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Koichiro Yoshimaru
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Tomoaki Taguchi
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
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25
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Athanasiou A, Papalois A, Kontos M, Griniatsos J, Liakopoulos D, Spartalis E, Agrogiannis G, Liakakos T, Pikoulis E. The beneficial role of simultaneous splenectomy after extended hepatectomy: experimental study in pigs. J Surg Res 2016; 208:121-131. [PMID: 27993199 DOI: 10.1016/j.jss.2016.09.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Revised: 08/21/2016] [Accepted: 09/01/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND The role of hepatic hemodynamic modulation in the development of "small-for-size" syndrome (SFSS) after extended hepatectomy (EH) or living-donor liver transplantation is still controversial. We have designed an experimental study to investigate the effect of hemodynamic parameters of the liver circulation on the development of SFSS after EH in a porcine model. METHODS Eighteen pigs were randomly divided into two groups: group A has received EH (75%-80%) without splenectomy, and group B with EH and simultaneous splenectomy was carried out. Portal hemodynamics, liver function tests, histologic findings, injury and survival rates were compared between groups A and B. RESULTS The 7-d survival rate in the splenectomy group was significantly improved compared with group A (88.9% versus 44.4%, P < 0.05). Portal vein pressure, portal vein flow, and liver function tests in the splenectomy group were significantly lower than in group A immediately after splenectomy and postoperatively until the day of sacrifice. Histologic findings in group A clearly illustrate severe inflammation, bridging necrosis, ischemic cholangitis, and severe congestion, while in group B there were less serious histologic changes. CONCLUSIONS Our experimental study indicates that perioperative portal modulation can successfully prevent the manifestation of SFSS after EH. Therefore, by focusing on "flow" rather than on "size," researchers may understand better the pathophysiology of this syndrome.
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Affiliation(s)
- Antonios Athanasiou
- First Surgery Department, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece.
| | | | - Michael Kontos
- First Surgery Department, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - John Griniatsos
- First Surgery Department, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Liakopoulos
- First Surgery Department, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Eleftherios Spartalis
- First Surgery Department, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Theodoros Liakakos
- First Surgery Department, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Emmanouil Pikoulis
- First Surgery Department, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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26
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Yamada S, Morine Y, Imura S, Ikemoto T, Arakawa Y, Iwahashi S, Saito Y, Yoshikawa M, Teraoku H, Shimada M. Liver regeneration after splenectomy in patients with liver cirrhosis. Hepatol Res 2016; 46:443-9. [PMID: 26428414 DOI: 10.1111/hepr.12573] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Revised: 08/04/2015] [Accepted: 08/10/2015] [Indexed: 02/08/2023]
Abstract
AIM Splenectomy is a well-known procedure to improve thrombocytopenia and liver function in patients with liver cirrhosis (LC). However, the effect of splenectomy on liver regeneration remains unclear. The aim of this study is to investigate the effect of splenectomy on liver regeneration. METHODS Twenty patients with LC who underwent splenectomy were included in this study. Liver and splenic volumes were measured by a 3-D simulation imaging system. Liver volume (LV) and clinicopathological data were compared before and 6 months after splenectomy. Thereafter, patients were divided into two groups: the elevated LV group and the reduced LV group. Patient characteristics were compared between the two groups. RESULTS Postoperative LV was increased in 14 patients compared with the preoperative state. Thrombocytopenia, leukopenia, total bilirubin and prothrombin time were improved after splenectomy. In the elevated LV group, four patients exhibited improved Child-Pugh grades after splenectomy, whereas no patients demonstrated improvement in the reduced LV group. The elevated LV group exhibited high albumin level, good indocyanine green retention rate at 15 min and large splenic volume compared with the same measurements in the decreased group. Patients with larger spleen volumes and higher albumin values before splenectomy showed increased rates of LV after splenectomy. CONCLUSION Splenectomy for patients with LC improved pancytopenia and liver function. Especially, in patients with large spleen and high albumin levels, considerable increases in LV and improved liver function were observed.
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Affiliation(s)
- Shinichiro Yamada
- Department of Surgery, The University of Tokushima, Tokushima City, Japan
| | - Yuji Morine
- Department of Surgery, The University of Tokushima, Tokushima City, Japan
| | - Satoru Imura
- Department of Surgery, The University of Tokushima, Tokushima City, Japan
| | - Tetsuya Ikemoto
- Department of Surgery, The University of Tokushima, Tokushima City, Japan
| | - Yusuke Arakawa
- Department of Surgery, The University of Tokushima, Tokushima City, Japan
| | - Shuichi Iwahashi
- Department of Surgery, The University of Tokushima, Tokushima City, Japan
| | - Yu Saito
- Department of Surgery, The University of Tokushima, Tokushima City, Japan
| | - Masato Yoshikawa
- Department of Surgery, The University of Tokushima, Tokushima City, Japan
| | - Hiroki Teraoku
- Department of Surgery, The University of Tokushima, Tokushima City, Japan
| | - Mitsuo Shimada
- Department of Surgery, The University of Tokushima, Tokushima City, Japan
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27
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Li N, Wang Z, Lin J. Up-regulated expression of PTEN after splenetomy may prevent the progression of liver fibrosis in rats. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2015; 23:50-56. [PMID: 26545563 DOI: 10.1002/jhbp.300] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 11/04/2015] [Indexed: 01/04/2023]
Abstract
BACKGROUND/PURPOSE To investigate the mechanisms of delaying progression of liver fibrosis by splenectomy. METHODS Liver fibrosis was induced by common bile duct ligation. Rats were divided into 3 groups randomly: group A with common bile duct ligation and splenectomy (n = 45), group B with common bile duct ligation and spleen sham operation (n = 45), group C with sham common bile duct ligation and spleen sham operation (n = 45). Liver samples were collected at the 1st, 3rd and 5th week. H&E staining and Sirius staining were used to evaluate the degree of liver fibrosis, immunohistochemical staining was used to measure the expression of α-SMA and PTEN. PTEN mRNA and protein expression was measured by real-time PCR and Western-blot. RESULTS Over time, liver fibrosis developed gradually in group A and B. The expression of PTEN mRNA and protein in group A was higher than that in group B (P < 0.05), while the expression of α-SMA was higher in group B (P < 0.05). The expression of PTEN was negatively correlated with α-SMA (r = -0.86, P < 0.05). CONCLUSIONS In this study, splenectomy can up-regulate the expression of PTEN and reduce the secretion of α-SMA, thereby deterring the progression of liver fibrosis.
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Affiliation(s)
- Naishu Li
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Ziming Wang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jianhua Lin
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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Miyashita T, Nakanuma S, Ahmed AK, Makino I, Hayashi H, Oyama K, Nakagawara H, Tajima H, Takamura H, Ninomiya I, Fushida S, Harmon JW, Ohta T. Ischemia reperfusion-facilitated sinusoidal endothelial cell injury in liver transplantation and the resulting impact of extravasated platelet aggregation. Eur Surg 2015; 48:92-98. [PMID: 27110233 PMCID: PMC4830883 DOI: 10.1007/s10353-015-0363-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Revised: 09/28/2015] [Accepted: 09/29/2015] [Indexed: 12/13/2022]
Abstract
Background The exact sequence of events leading to ultimate hepatocellular damage following ischemia/reperfusion (I/R) is incompletely understood. In this article, we review a mechanism of organ dysfunction after hepatic I/R or immunosuppressive treatment, in addition to the potential of liver sinusoidal endothelial cell (LSEC) protection and antiplatelet treatment for the suppression of hepatocellular damage. Methods A review of the literature, utilizing PubMed-NCBI, was used to provide information on the components necessary for the development of hepatocellular damage following I/R. Results It is well-established that LSECs damage following hepatic I/R or immunosuppressive treatment followed by extravasated platelet aggregation (EPA) is the root cause of organ dysfunction in liver transplantation. We have classified three phases, from LSECs damage to organ dysfunction, utilizing the predicted pathogenic mechanism of sinusoidal obstruction syndrome. The first phase is detachment of LSECs and sinusoidal wall destruction after LSECs injury by hepatic I/R or immunosuppressive treatment. The second phase is EPA, accomplished by sinusoidal wall destruction. The various growth factors, including thromboxane A2, serotonin, transforming growth factor-beta and plasminogen activator inhibitor-1, released by EPA in the Disse’s space of zone three, induce portal hypertension and the progression of hepatic fibrosis. The third phase is organ dysfunction following portal hypertension, hepatic fibrosis, and suppressed liver regeneration through various growth factors secreted by EPA. Conclusion We suggest that EPA in the space of Disse, initiated by LSECs damage due to hepatic I/R or immunosuppressive treatment, and activated platelets may primarily contribute to liver damage in liver transplantation. Endothelial protective therapy or antiplatelet treatment may be useful in the treatment of hepatic I/R following EPA.
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Affiliation(s)
- T Miyashita
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - S Nakanuma
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - A K Ahmed
- Department of Surgery, Johns Hopkins University School of Medicine, 4940 Eastern Avenue, 21224 Baltimore, MD USA
| | - I Makino
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - H Hayashi
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - K Oyama
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - H Nakagawara
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - H Tajima
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - H Takamura
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - I Ninomiya
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - S Fushida
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
| | - J W Harmon
- Department of Surgery, Johns Hopkins University School of Medicine, 4940 Eastern Avenue, 21224 Baltimore, MD USA
| | - T Ohta
- Department of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takaramachi, 920-8641 Kanazawa, Ishikawa Japan
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Yamamoto N, Okano K, Oshima M, Akamoto S, Fujiwara M, Tani J, Miyoshi H, Yoneyama H, Masaki T, Suzuki Y. Laparoscopic splenectomy for patients with liver cirrhosis: Improvement of liver function in patients with Child-Pugh class B. Surgery 2015; 158:1538-44. [PMID: 26070848 DOI: 10.1016/j.surg.2015.05.008] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 04/24/2015] [Accepted: 05/09/2015] [Indexed: 12/21/2022]
Abstract
BACKGROUND We aimed to assess the short-term outcomes of laparoscopic splenectomy (LS) and liver function at 1 year after splenectomy in the patients with liver cirrhosis. METHODS Forty-five patients with liver cirrhosis and hypersplenism underwent LS. We reviewed electronic medical records regarding the liver functional reserve, the etiology of liver cirrhosis, and the presence of hepatocellular carcinoma and esophago-gastric varices. Prospectively collected data of perioperative variables, postoperative complications, and long-term liver function were analyzed. RESULTS Forty-five patients had a chronic liver disease classified into Child-Pugh classes (A/B/C: 23/20/2). The etiologies of disease were hepatitis C virus infection in 34 patients, hepatitis B virus infection in 4, and others in 7. Fourteen patients underwent procedures in addition to LS, including hepatectomy (n = 7) and devascularization for esophagogastric varices (n = 8). Postoperative complications occurred in 11 patients (24%). Neither postoperative liver failure nor in-hospital mortality occurred. White blood cell and platelet counts determined 7 days, 1 month, and 1 year after LS doubled or increased more than twice compared with the preoperative values (P < .001). One year after LS, patients who had been classified preoperatively into Child-Pugh class B had decreased total serum bilirubin levels (P = .03), and increased prothrombin activity (P = 003) and decreased Child-Pugh scores (P = .001). The Child-Pugh classifications improved in 14 of 18 patients (78%) who had Child-Pugh class B preoperatively. CONCLUSION LS is a safe and feasible procedure for hypersplenism in patients with liver cirrhosis. In addition, LS most likely ameliorates liver function at 1 year after LS in patients with Child-Pugh class B liver cirrhosis.
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Affiliation(s)
- Naoki Yamamoto
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan.
| | - Keiichi Okano
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Minoru Oshima
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Shitaro Akamoto
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Masao Fujiwara
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Hisaaki Miyoshi
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Yasuyuki Suzuki
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan
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Zhang XY, Li C, Wen TF, Yan LN, Li B, Yang JY, Wang WT, Jiang L. Synchronous splenectomy and hepatectomy for patients with hepatocellular carcinoma and hypersplenism: A case-control study. World J Gastroenterol 2015; 21:2358-2366. [PMID: 25741142 PMCID: PMC4342911 DOI: 10.3748/wjg.v21.i8.2358] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 10/07/2014] [Accepted: 11/11/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether the use of synchronous hepatectomy and splenectomy (HS) is more effective than hepatectomy alone (HA) for patients with hepatocellular carcinoma (HCC) and hypersplenism.
METHODS: From January 2007 to March 2013, 84 consecutive patients with HCC and hypersplenism who underwent synchronous hepatectomy and splenectomy in our center were compared with 84 well-matched patients from a pool of 268 patients who underwent hepatectomy alone. The short-term and long-term outcomes of the two groups were analyzed and compared.
RESULTS: The mean time to recurrence was 21.11 ± 12.04 mo in the HS group and 11.23 ± 8.73 mo in the HA group, and these values were significantly different (P = 0.001). The 1-, 3-, 5-, and 7-year disease-free survival rates for the patients in the HS group and the HA group were 86.7%, 70.9%, 52.7%, and 45.9% and 88.1%, 59.4%, 43.3%, and 39.5%, respectively (P = 0.008). Platelet and white blood cell counts in the HS group were significantly increased compared with the HA group one day, one week, one month and one year postoperatively (P < 0.001). Splenectomy and micro-vascular invasion were significant independent prognostic factors for disease-free survival. Gender, tumor number, and recurrence were independent prognostic factors for overall survival.
CONCLUSION: Synchronous hepatectomy and hepatectomy potentially improves disease-free survival rates and alleviates hypersplenism without increasing the surgical risks for patients with HCC and hypersplenism.
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Lee SC, Jeong HJ, Choi BJ, Kim SJ. Role of the spleen in liver regeneration in relation to transforming growth factor-β1 and hepatocyte growth factor. J Surg Res 2015; 196:270-7. [PMID: 25862490 DOI: 10.1016/j.jss.2015.02.025] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Revised: 01/29/2015] [Accepted: 02/12/2015] [Indexed: 10/24/2022]
Abstract
BACKGROUND Optimizing the hepatic regenerative capacity is an immediate priority after partial hepatectomy (PH). Recent reports have indicated improvement in liver regeneration after splenectomy, raising interest on the role of the spleen in liver regeneration. However, little is known about the exact mechanism underlying these effects. MATERIALS AND METHODS Eight-week-old male Sprague-Dawley rats randomly underwent either 70% PH only (PH, n = 25) or 70% PH combined with splenectomy (PHS, n = 25). The specimens, including liver and/or spleen tissues and sera, were collected and evaluated using immunohistochemistry, Western blotting, enzyme-linked immunosorbent assay, and serum biochemical analyses. RESULTS PH induced higher transforming growth factor (TGF)-β1 expression in the liver up to 72 h after PH. The PHS group showed significantly higher numbers of proliferating cell nuclear antigen-positive cells, reflecting higher liver regeneration and lower amounts of liver enzymes compared with the PH group. Splenectomy after PH resulted in increased and decreased serum concentrations of hepatocyte growth factor (HGF) and TGF-β1 in the portal vein, respectively. Moreover, the PHS group demonstrated downregulation of TGF-β1 and its receptor TGF-β-RII and upregulation of HGF and its receptor c-Met in the liver. CONCLUSIONS The spleen seemed to exhibit an inhibitory effect on liver regeneration by upregulating TGF-β1 and its receptor TGF-β-RII and downregulating HGF and its receptor c-Met in the liver. Therefore, splenectomy can be considered an option for improving liver regeneration in selected patients with reduced regenerative capacity of the liver.
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Affiliation(s)
- Sang Chul Lee
- Department of Surgery, Daejeon St. Mary's Hospital, The Catholic University of Korea, Daejeon, Republic of Korea
| | - Hye Jin Jeong
- Department of Surgery, Daejeon St. Mary's Hospital, The Catholic University of Korea, Daejeon, Republic of Korea
| | - Byung-Jo Choi
- Department of Surgery, Daejeon St. Mary's Hospital, The Catholic University of Korea, Daejeon, Republic of Korea
| | - Say-June Kim
- Department of Surgery, Daejeon St. Mary's Hospital, The Catholic University of Korea, Daejeon, Republic of Korea.
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Nakanuma S, Miyashita T, Hayashi H, Tajima H, Takamura H, Tsukada T, Okamoto K, Sakai S, Makino I, Kinoshita J, Nakamura K, Oyama K, Inokuchi M, Nakagawara H, Ninomiya I, Kitagawa H, Fushida S, Fujimura T, Ohta T. Extravasated platelet aggregation in liver zone 3 may correlate with the progression of sinusoidal obstruction syndrome following living donor liver transplantation: A case report. Exp Ther Med 2015; 9:1119-1124. [PMID: 25780397 PMCID: PMC4353807 DOI: 10.3892/etm.2015.2245] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2014] [Accepted: 01/05/2015] [Indexed: 12/15/2022] Open
Abstract
Sinusoidal obstruction syndrome (SOS), previously known as veno-occlusive disease, is relatively rare subsequent to liver transplantation (LT). SOS refractory to medical therapy, however, can result in centrilobular fibrosis, portal hypertension and liver failure. Although sinusoidal endothelial cell damage around central venules (zone 3) occurs early in the development of SOS, the detailed mechanism of SOS development and its association with thrombocytopenia are not yet completely understood. The present report describes a patient who experienced SOS with unexplained thrombocytopenia following living donor LT. The progression of SOS resulted in graft dysfunction and the patient succumbed. The presence of platelets in the liver allograft was assayed immunohistochemically using antibody to the platelet marker cluster of differentiation 42b (platelet glycoprotein Ib). Platelet aggregates were found attached to hepatocytes along the sinusoid and within the cytoplasm of hepatocytes, particularly in zone 3. By contrast, no staining was observed in zone 1. These findings suggested that extravasated platelet aggregation in the space of Disse and the phagocytosis of platelets by hepatocytes were initiated by sinusoidal endothelial cell damage due to the toxicity of the immunosuppressant tacrolimus or a corticosteroid pulse, and that platelet activation and degranulation may be at least partially involved in the mechanism responsible for SOS.
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Affiliation(s)
- Shinichi Nakanuma
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Tomoharu Miyashita
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Hironori Hayashi
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Hidehiro Tajima
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Hiroyuki Takamura
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Tomoya Tsukada
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Koichi Okamoto
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Seisho Sakai
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Isamu Makino
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Jun Kinoshita
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Keishi Nakamura
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Katsunobu Oyama
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Masafumi Inokuchi
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Hisatoshi Nakagawara
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Itasu Ninomiya
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Hirohisa Kitagawa
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Sachio Fushida
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Takashi Fujimura
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Tetsuo Ohta
- Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
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Cetta F, Fusai G, Malagò M. Liver Pathophysiology: Liver Regeneration, Vascular Alterations, and Ischemia/Reperfusion. BENIGN TUMORS OF THE LIVER 2015:35-45. [DOI: 10.1007/978-3-319-12985-3_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Spleen: promised land for new and novel interventions? Cardiovasc Intervent Radiol 2014; 38:501-2. [PMID: 25424043 DOI: 10.1007/s00270-014-1029-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2014] [Accepted: 10/10/2014] [Indexed: 10/24/2022]
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Asanoma M, Ikemoto T, Mori H, Utsunomiya T, Imura S, Morine Y, Iwahashi S, Saito Y, Yamada S, Shimada M. Cytokine expression in spleen affects progression of liver cirrhosis through liver-spleen cross-talk. Hepatol Res 2014; 44:1217-23. [PMID: 24506078 DOI: 10.1111/hepr.12267] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 10/22/2013] [Accepted: 10/28/2013] [Indexed: 12/19/2022]
Abstract
AIM It is unclear whether the spleen affects the progression of liver cirrhosis (LC) through "liver-spleen cross-talk". Transforming growth factor-β1 (TGF-β1) is reported to be the most potent cytokine of liver fibrosis, and interleukin-6 (IL-6) is an important factor of liver regeneration. In this study, we investigated the expression of cytokines in the spleens of LC patients in order to attempt to prove the existence of liver-spleen cross-talk. METHODS The study enrolled 22 patients who underwent splenectomy at our institute between 2004 and 2010. TGF-β1 expression in the resected spleen was measured using immunohistochemical staining. Two-color immunofluorescent staining for CD68 and TGF-β1 in the spleen was performed to detect sources of TGF-β1. IL-6 expression in the spleen was measured by reverse transcription polymerase chain reaction. RESULTS TGF-β1 expression was significantly higher in the spleens of LC patients than in those of patients with normal livers (P < 0.05). Coexpression of CD68 and TGF-β1 was confirmed. The expression of IL-6 in the spleens of LC patients was significantly lower than that in patients with normal livers (P < 0.05). CONCLUSION TGF-β1 produced by macrophages and cytokines such as IL-6 could affect the progression of liver fibrosis and regeneration in patients with LC via liver-spleen cross-talk.
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Kondo R, Kage M, Ogata T, Nakashima O, Akiba J, Nomura Y, Yano H. Therapeutic efficacy of splenectomy is attenuated by necroinflammation of the liver in patients with liver cirrhosis. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2014; 22:217-24. [DOI: 10.1002/jhbp.177] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Reiichiro Kondo
- Department of Pathology; Kurume University School of Medicine; 67 Asahi-machi Kurume Fukuoka 830-0011 Japan
- Cancer Center; Kurume University Hospital; Kurume Fukuoka Japan
- Department of Diagnostic Pathology; Kurume University Hospital; Kurume Fukuoka Japan
| | - Masayoshi Kage
- Cancer Center; Kurume University Hospital; Kurume Fukuoka Japan
- Department of Diagnostic Pathology; Kurume University Hospital; Kurume Fukuoka Japan
| | - Toshiro Ogata
- Department of Surgery; Kurume University School of Medicine; Kurume Fukuoka Japan
| | - Osamu Nakashima
- Department of Clinical Laboratory Medicine; Kurume University Hospital; Kurume Fukuoka Japan
| | - Jun Akiba
- Department of Pathology; Kurume University School of Medicine; 67 Asahi-machi Kurume Fukuoka 830-0011 Japan
| | - Yoriko Nomura
- Department of Pathology; Kurume University School of Medicine; 67 Asahi-machi Kurume Fukuoka 830-0011 Japan
- Department of Diagnostic Pathology; Kurume University Hospital; Kurume Fukuoka Japan
| | - Hirohisa Yano
- Department of Pathology; Kurume University School of Medicine; 67 Asahi-machi Kurume Fukuoka 830-0011 Japan
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Yoichi T, Takayashiki T, Shimizu H, Yoshidome H, Ohtsuka M, Kato A, Yoshitomi H, Furukawa K, Kuboki S, Okamura D, Suzuki D, Nakajima M, Miyazaki M. Protective effects of simultaneous splenectomy on small-for-size liver graft injury in rat liver transplantation. Transpl Int 2013; 27:106-13. [DOI: 10.1111/tri.12223] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Revised: 04/20/2013] [Accepted: 10/20/2013] [Indexed: 12/17/2022]
Affiliation(s)
- Takuya Yoichi
- Department of General Surgery; Graduate School of Medicine; Chiba University; Chiba Japan
| | - Tsukasa Takayashiki
- Department of General Surgery; Graduate School of Medicine; Chiba University; Chiba Japan
| | - Hiroaki Shimizu
- Department of General Surgery; Graduate School of Medicine; Chiba University; Chiba Japan
| | - Hiroyuki Yoshidome
- Department of General Surgery; Graduate School of Medicine; Chiba University; Chiba Japan
| | - Masayuki Ohtsuka
- Department of General Surgery; Graduate School of Medicine; Chiba University; Chiba Japan
| | - Atsushi Kato
- Department of General Surgery; Graduate School of Medicine; Chiba University; Chiba Japan
| | - Hideyuki Yoshitomi
- Department of General Surgery; Graduate School of Medicine; Chiba University; Chiba Japan
| | - Katsunori Furukawa
- Department of General Surgery; Graduate School of Medicine; Chiba University; Chiba Japan
| | - Satoshi Kuboki
- Department of General Surgery; Graduate School of Medicine; Chiba University; Chiba Japan
| | - Daiki Okamura
- Department of General Surgery; Graduate School of Medicine; Chiba University; Chiba Japan
| | - Daisuke Suzuki
- Department of General Surgery; Graduate School of Medicine; Chiba University; Chiba Japan
| | - Masayuki Nakajima
- Department of General Surgery; Graduate School of Medicine; Chiba University; Chiba Japan
| | - Masaru Miyazaki
- Department of General Surgery; Graduate School of Medicine; Chiba University; Chiba Japan
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Arakawa Y, Shimada M, Utsunomya T, Imura S, Morine Y, Ikemoto T, Takasu C. Effects of splenectomy on hepatic gene expression profiles after massive hepatectomy in rats. J Gastroenterol Hepatol 2013; 28:1669-77. [PMID: 23808869 DOI: 10.1111/jgh.12316] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/21/2013] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Possible spleno-hepatic relationships affected by hepatectomy still remained unclear. We have previously reported that splenectomy may ameliorate liver injuries and promote appropriate liver regeneration after massive hepatectomy. Therefore, we investigated the effects of splenectomy on the DNA expression profile in the liver after massive hepatectomy in rats. METHODS Rats were divided into the following two groups: 90% hepatectomy (Hx group) and 90% hepatectomy with splenectomy (Hx + Sp group). Rats were sacrificed 3 and 6 h after surgery, and mRNA from liver tissue was isolated and hybridized to Affymetrix GeneChip Rat Genome 230 2.0 Array (Affymetrix, Santa Clara, CA, USA) and a pathway analysis was done with Ingenuity Pathway Analysis (Ingenuity Systems, Mountain View, CA, USA). RESULTS We determined the Hx + Sp/Hx ratio to assess the influence of splenectomy, and cut-off values were set at more than 2.0-fold or less than 1/2 (0.5)-fold. Immediate early response gene including early growth response-1 and FBJ murine osteosarcoma-related pathways were markedly downregulated by splenectomy. In contrast, heme oxygenase-1 gene-related pathway was upregulated by splenectomy. CONCLUSIONS Splenectomy provided the protective effects for liver failure and promoted liver regeneration, possibly owing to the downregulation of immediate early response genes and upregulation of the heat shock protein, heme oxygenase-1.
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Affiliation(s)
- Yusuke Arakawa
- The Department of Surgery, Institute of Health Biosciences, The University of Tokushima, Tokushima, Japan
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Kim SJ, Na GH, Choi HJ, You Y, Kim DG. Effect of donor right hepatectomy on splenic volume and platelet count for living donor liver transplantation. J Gastrointest Surg 2013; 17:1576-83. [PMID: 23838887 DOI: 10.1007/s11605-013-2219-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2012] [Accepted: 04/24/2013] [Indexed: 01/31/2023]
Abstract
BACKGROUND Donor hepatectomy for living donor liver transplantation accompanies physio-morphological changes of the liver and spleen. Therefore, the long-term consequences of these organs should be characterized to ensure donor's safety. METHODS A total of 382 right liver harvests for liver transplantation were performed from October 2000 to February 2011. Clinical parameters across donor operations were compared, and the associations were investigated. RESULTS The remaining liver grew continually, reaching 81.5 ± 11.2% of the entire liver until 6 months after donation. The spleen grew to 143.1 ± 28.8% of the pre-donation value within 1 week after surgery, and thereafter, its size decreased gradually to 130.6 ± 25.1% at 6 months. At 6 months post-donation, 48.1% (114/237) of donors showed an increase of ≥30% in splenic volume, and 15.9% (50/315) of donors exhibited a decrease of ≥30% in platelet count. However, patients with splenic enlargement and/or decrease in platelet count at 6 months post-donation were not different in liver function, liver regeneration, or overall complications. CONCLUSIONS Although splenic enlargement and/or decrease in platelet count can persist for more than 6 months after donation in patient population after donor right hepatectomy, such a change did not impact donor's safety.
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Affiliation(s)
- Say-June Kim
- Department of Surgery, Daejeon St. Mary's Hospital, The Catholic University of Korea, Daejeon, South Korea
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Wang QM, Duan ZJ, Du JL, Guo SB, Sun XY, Liu Z. Heme oxygenase/carbon monoxide pathway inhibition plays a role in ameliorating fibrosis following splenectomy. Int J Mol Med 2013; 31:1186-94. [PMID: 23525258 DOI: 10.3892/ijmm.2013.1309] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Accepted: 02/22/2013] [Indexed: 11/06/2022] Open
Abstract
Splenectomy is a recognized therapy for liver cirrhosis with splenomegaly, since it decreases free iron concentration that accompanies the destruction of red blood cells. Heme oxygenase (HO)-1 and its by-products, iron and carbon monoxide (CO), play crucial roles in hepatic fibrosis. The aim of the present study was to determine whether splenectomy in cirrhotic rats induced by bile duct ligation (BDL), through the HO/CO pathway, could slow down the development of liver fibrosis. Male Sprague-Dawley rats were divided randomly into the sham, BDL, splenectomy, Fe, zinc protoporphyrin (Znpp) and cobalt protoporphyrin (Copp) treatment groups, for inhibiting and inducing HO-1 expression. The level of HO-1 was detected by western blot analysis and reverse transcription-polymerase chain reaction. Serum carboxyhemoglobin (COHb), iron and portal vein pressure (PVP) were also quantified. Liver iron was measured by atomic absorption spectrometry with acetylene-air flame atomization. HO-1 and α-smooth muscle actin (α-SMA) were localized by immunohistochemistry. Liver and spleen iron were visualized by Perls' Prussian blue staining. Hepatic fibrosis was assessed using hematoxylin and eosin (H&E) staining. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum transforming growth factor-β1 (TGF-β1). The results showed that liver, spleen and serum levels of HO-1, COHb and iron were greatly enhanced in the BDL group compared with the sham group; they were reduced following splenectomy and Znpp treatment, but were elevated in the Copp and Fe groups. Hydroxyproline, TGF-β1, α-SMA, PVP and malonaldehyde levels were lower in the splenectomy and Znpp groups compared to BDL, while higher levels were observed in the Copp and Fe-treated groups. Our study shows that splenectomy reduces iron and CO levels in part by reducing HO-1 expression, and it decreases portal pressure and slightly decreases hepatic fibroproliferation.
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Affiliation(s)
- Qiu-Ming Wang
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
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Do N, Zhao R, Ray K, Ho K, Dib M, Ren X, Kuzontkoski P, Terwilliger E, Karp SJ. BMP4 is a novel paracrine inhibitor of liver regeneration. Am J Physiol Gastrointest Liver Physiol 2012; 303:G1220-7. [PMID: 23019195 PMCID: PMC3532457 DOI: 10.1152/ajpgi.00105.2012] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Transforming growth factor (TGF)-β family members exert strong effects on restoration of liver mass after injury. Bone morphogenetic proteins (BMPs) are members of the TGF-β family and are found in the liver, suggesting that these proteins may play a role in liver regeneration. We examined BMP signaling in the liver during hepatectomy. We found that BMP4 is constitutively expressed in the peribiliary stroma and endothelial cells of the liver and that expression is decreased after hepatectomy. Mice driven to maintain BMP4 expression in the liver display inhibited hepatocyte proliferation and restoration of liver mass after hepatectomy, suggesting that reduced BMP4 is necessary for normal regeneration. Consistent with this finding, hepatocyte-specific deletion of the BMP receptor activin receptor-like kinase 3 (Alk3) enhances regeneration and reduces phosphorylation of SMAD1/5/8, a transducer of BMP signaling. In contrast to experiments in wild-type mice, maintaining BMP4 levels has no effect on liver regeneration in hepatocyte-specific Alk3 null mice, providing evidence that BMP4 signals through Alk3 to inhibit liver regeneration. Consistent with these findings, the BMP4 antagonist Noggin enhances regeneration. Furthermore, high-dose BMP4 inhibits proliferation of primary hepatocytes and HepG2 cells in culture. These findings elucidate a new, potentially clinically relevant paradigm in which a constitutively expressed paracrine inhibitory factor plays a critical role in liver regeneration.
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Affiliation(s)
- Nhue Do
- 1Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts;
| | - Rong Zhao
- 1Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts;
| | - Kevin Ray
- 2Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee;
| | - Karen Ho
- 3Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts; and
| | - Martin Dib
- 1Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts;
| | - Xianghui Ren
- 4Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Paula Kuzontkoski
- 4Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Ernest Terwilliger
- 4Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Seth J. Karp
- 2Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee;
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Kuriyama N, Isaji S, Kishiwada M, Ohsawa I, Hamada T, Mizuno S, Usui M, Sakurai H, Tabata M, Yamada T. Dual cytoprotective effects of splenectomy for small-for-size liver transplantation in rats. Liver Transpl 2012; 18:1361-1370. [PMID: 22847861 DOI: 10.1002/lt.23519] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Accepted: 07/15/2012] [Indexed: 02/07/2023]
Abstract
The problems associated with small-for-size liver grafts (ie, high mortality rates, postoperative complications, and acute rejection) remain critical issues in partial orthotopic liver transplantation (OLT). In association with partial OLT, splenectomy (SP) is a procedure used to reduce the portal pressure. However, the precise effects of SP on partial OLT have been unclear. In this study, using small-for-size liver grafts in rats, we examined the cytoprotective effects of SP on OLT. Liver grafts were assigned to 2 groups: a control group (OLT alone) and an SP group (OLT after SP). SP significantly increased animal survival and decreased liver damage. SP exerted the following cytoprotective effects: (1) it improved hepatic microcirculation and prevented increases in the portal pressure after OLT, (2) it suppressed the hepatic infiltration of neutrophils and macrophages through the direct elimination of splenic inflammatory cells before OLT, (3) it decreased the hepatic expression of tumor necrosis factor α and interleukin-6, (4) it attenuated sinusoidal endothelial injury, (5) it decreased plasma endothelin 1 levels and increased hepatic heme oxygenase 1 expression, (6) it suppressed hepatocellular apoptosis through the down-regulation of hepatic caspase-3 and caspase-8 activity, and (7) it increased hepatic regeneration. In conclusion, SP for small-for-size grafts exerts dual cytoprotective effects by preventing excessive portal vein hepatic inflow and eliminating splenic inflammatory cell recruitment into the liver; this in turn inhibits hepatocellular apoptosis and improves liver regeneration.
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Affiliation(s)
- Naohisa Kuriyama
- Departments of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Mie, Japan.
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Hayashi H, Takamura H, Yamaguchi Y, Shoji Y, Nakagawara H, Tajima H, Onishi I, Kitagawa H, Tani T, Kayahara M, Ohta T. Recent role of Hassab's operation for cirrhotic patients: Combination with endoscopic procedure for varices. Asian J Surg 2012; 35:57-61. [DOI: 10.1016/j.asjsur.2012.04.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2011] [Revised: 11/13/2011] [Accepted: 12/14/2011] [Indexed: 11/29/2022] Open
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Kim J, Kim CJ, Ko IG, Joo SH, Ahn HJ. Splenectomy affects the balance between hepatic growth factor and transforming growth factor-β and its effect on liver regeneration is dependent on the amount of liver resection in rats. JOURNAL OF THE KOREAN SURGICAL SOCIETY 2012; 82:238-45. [PMID: 22493765 PMCID: PMC3319778 DOI: 10.4174/jkss.2012.82.4.238] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2011] [Revised: 01/03/2012] [Accepted: 02/02/2012] [Indexed: 01/15/2023]
Abstract
Purpose Small-for-size syndrome (SFSS) is a major problem in liver surgery, and splenectomy has been used to prevent SFSS. However, it is unknown whether splenectomy has the same effect on liver regeneration in both standard and marginal hepatectomy. The aim of this study is to see a difference in effect of splenectomy on liver regeneration according to the amount of liver resection. Methods Thirty male Sprague-Dawley rats (220 to 260 g) were divided into the following five groups: control (n = 6), 70% hepatectomy (n = 6), 70% hepatectomy with splenectomy (n = 6), 90% hepatectomy (n = 6), and 90% hepatectomy with splenectomy (n = 6). The animals were euthanized 24 hours after surgery and liver specimens were obtained. To assess liver regeneration, we performed immunohistochemistry of liver tissue using 5-bromo-2-deoxyuridine (BrdU) labeling and Western blot analysis of hepatic growth factor (HGF) and transforming growth factor-β (TGF-β) in the liver tissue. Results The splenectomized subgroup had a higher BrdU-positive cell count in the 90% hepatectomy group, but not in the 70% hepatectomy group (P < 0.001). Splenectomy significantly decreased TGF-β expression (P = 0.005) and increased the HGF to TGF-β ratio (P = 0.002) in the 90% hepatectomy group, but not in the 70% hepatectomy group. Conclusion The positive effect of splenectomy on liver regeneration was greater in the group with the larger liver resection. This phenomenon may be related to the relative balance between HGF and TGF-β in the liver.
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Affiliation(s)
- Joohyun Kim
- Department of Surgery, Kyung Hee University School of Medicine, Seoul, Korea
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Ren YS, Qian NS, Tang Y, Liao YH, Liu WH, Raut V, Tao KS, Dou KF. Beneficial effects of splenectomy on liver regeneration in a rat model of massive hepatectomy. Hepatobiliary Pancreat Dis Int 2012; 11:60-65. [PMID: 22251471 DOI: 10.1016/s1499-3872(11)60126-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Small-for-size syndrome is a widely recognized clinical complication after living donor liver transplantation or extended hepatectomy due to inadequate liver mass. The purpose of this study was to investigate the role of splenectomy in rats after massive hepatectomy, a surrogate model of small-for-size graft. METHODS Rats were divided into eight groups, each with 20 animals: 50% hepatectomy (50% Hx), 50% hepatectomy+splenectomy (50% Hx+Sp), 60% Hx, 60% Hx+Sp, 70% Hx, 70% Hx+Sp, 90% Hx and 90% Hx+Sp. The following parameters were evaluated: liver function tests (ALT, AST and TBIL), liver regeneration ratio, DNA synthesis, proliferation cell nuclear antigen, hepatic oxygen delivery (HDO2) and hepatic oxygen consumption (HVO2). RESULTS The liver regeneration ratio was enhanced in the Hx+Sp groups (P<0.05). In addition, compared with the Hx groups, the Hx+Sp groups had better liver functions (P<0.05). DNA synthesis and proliferation cell nuclear antigen were also increased in the Hx+Sp groups compared with the Hx groups (P<0.05). Furthermore, in the Hx+Sp groups, HDO2 and HVO2 were increased over those in the Hx groups (P<0.05), and were positively correlated with the liver regeneration ratio. CONCLUSIONS Splenectomy significantly improved liver function, and enhanced DNA synthesis and proliferation cell nuclear antigen after massive hepatectomy in rats. This operation could be mediated through increased HDO2 and HVO2, which facilitate liver regeneration.
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Affiliation(s)
- Yan-Shun Ren
- Department of Hepatobiliary Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an, China
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Fu Y, Zhang HB, Yang N, Zhu N, Si-Ma H, Chen W, Zhao WC, Yang GS. Porcine Partial Liver Transplantation Without Veno-venous Bypass: An Effective Model for Small-for-Size Liver Graft Injury. Transplant Proc 2011; 43:1953-61. [DOI: 10.1016/j.transproceed.2011.01.173] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2010] [Accepted: 01/11/2011] [Indexed: 02/07/2023]
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Kim J, Yi NJ, Shin WY, Kim T, Lee KU, Suh KS. Platelet transfusion can be related to liver regeneration after living donor liver transplantation. World J Surg 2010; 34:1052-8. [PMID: 20151125 DOI: 10.1007/s00268-010-0464-x] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Although liver regeneration is a fundamental aspect of living donor liver transplantation (LDLT), the factors that affect liver regeneration during the early post-transplantation period have not been thoroughly investigated. Recently it was suggested that platelets contribute to liver regeneration. The aim of the present study was to identify the major factors that affect liver graft regeneration during the early post-transplantation period. MATERIALS AND METHODS Eighty-seven right liver grafted, adult-to-adult LDLT patients were retrospectively analyzed. Liver regeneration was assessed by volumetry from computed tomographic (CT) scans obtained between the 9th and 11th postoperative days. The authors investigated relationships between clinical variables and liver graft regeneration rates, and they conducted multiple regression analysis on factors found to be significant by univariate analysis. RESULTS Mean graft weight at operation was 722.9 +/- 109.7 g, and mean graft volume assessed by follow-up CT was 1,042.2 +/- 155.6 ml, reflecting a mean liver graft regeneration of 45.9 +/- 22.3%. The graft regeneration was found to correlate inversely with graft-to-recipient weight ratio (GRWR, r = -0.406, p < 0.001) and directly with portal flow velocity (cm/s; r = 0.307; p = 0.004) and splenic index (cm(3); r = 0.282; p = 0.009). Moreover, the total amount (units) of platelets transfused was found to be significantly associated with graft regeneration (r = 0.293; p = -.006). Stepwise regression analysis showed that GRWR (beta = -33.124; p = 0.001), total amount of platelets transfused (beta = 0.771; p = 0.012), and splenic index (beta = -0.010; p = 0.049) were independently associated with graft regeneration. CONCLUSIONS The results of the present study suggest that platelets play a significant role in human liver regeneration after LDLT.
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Affiliation(s)
- Joohyun Kim
- Department of Surgery, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, 1 Hoegi-Dong, Dongdaemun-Gu, Seoul, 130-702, Republic of Korea
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Ho KJ, Do NL, Otu HH, Dib MJ, Ren X, Enjyoji K, Robson SC, Terwilliger EF, Karp SJ. Tob1 is a constitutively expressed repressor of liver regeneration. J Exp Med 2010; 207:1197-208. [PMID: 20513747 PMCID: PMC2882843 DOI: 10.1084/jem.20092434] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2009] [Accepted: 04/28/2010] [Indexed: 01/20/2023] Open
Abstract
How proliferative and inhibitory signals integrate to control liver regeneration remains poorly understood. A screen for antiproliferative factors repressed after liver injury identified transducer of ErbB2.1 (Tob1), a member of the PC3/BTG1 family of mito-inhibitory molecules as a target for further evaluation. Tob1 protein decreases after 2/3 hepatectomy in mice secondary to posttranscriptional mechanisms. Deletion of Tob1 increases hepatocyte proliferation and accelerates restoration of liver mass after hepatectomy. Down-regulation of Tob1 is required for normal liver regeneration, and Tob1 controls hepatocyte proliferation in a dose-dependent fashion. Tob1 associates directly with both Caf1 and cyclin-dependent kinase (Cdk) 1 and modulates Cdk1 kinase activity. In addition, Tob1 has significant effects on the transcription of critical cell cycle components, including E2F target genes and genes involved in p53 signaling. We provide direct evidence that levels of an inhibitory factor control the rate of liver regeneration, and we identify Tob1 as a crucial check point molecule that modulates the expression and activity of cell cycle proteins.
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Affiliation(s)
- Karen J. Ho
- Department of Surgery, Department of Medicine, and the Transplant Institute, Beth Israel Deaconess Medical Center, Boston, MA 02215
- Department of Surgery, Brigham and Women’s Hospital, Boston, MA 02115
| | - Nhue L. Do
- Department of Surgery, Department of Medicine, and the Transplant Institute, Beth Israel Deaconess Medical Center, Boston, MA 02215
- Department of Surgery, Brigham and Women’s Hospital, Boston, MA 02115
| | - Hasan H. Otu
- Department of Surgery, Department of Medicine, and the Transplant Institute, Beth Israel Deaconess Medical Center, Boston, MA 02215
| | - Martin J. Dib
- Department of Surgery, Department of Medicine, and the Transplant Institute, Beth Israel Deaconess Medical Center, Boston, MA 02215
| | - Xianghui Ren
- Department of Surgery, Department of Medicine, and the Transplant Institute, Beth Israel Deaconess Medical Center, Boston, MA 02215
| | - Keiichi Enjyoji
- Department of Surgery, Department of Medicine, and the Transplant Institute, Beth Israel Deaconess Medical Center, Boston, MA 02215
| | - Simon C. Robson
- Department of Surgery, Department of Medicine, and the Transplant Institute, Beth Israel Deaconess Medical Center, Boston, MA 02215
| | - Ernest F. Terwilliger
- Department of Surgery, Department of Medicine, and the Transplant Institute, Beth Israel Deaconess Medical Center, Boston, MA 02215
| | - Seth J. Karp
- Department of Surgery, Department of Medicine, and the Transplant Institute, Beth Israel Deaconess Medical Center, Boston, MA 02215
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Morinaga A, Ogata T, Kage M, Kinoshita H, Aoyagi S. Comparison of liver regeneration after a splenectomy and splenic artery ligation in a dimethylnitrosamine-induced cirrhotic rat model. HPB (Oxford) 2010; 12:22-30. [PMID: 20495641 PMCID: PMC2814400 DOI: 10.1111/j.1477-2574.2009.00116.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2009] [Accepted: 07/13/2009] [Indexed: 12/12/2022]
Abstract
AIM A splenectomy and splenic artery ligation accelerate liver regeneration and improve liver function after a hepatectomy. However, there are no studies that directly compared the effects of a splenectomy and splenic artery ligation. In the present study, we compared the effects of a splenectomy and splenic artery ligation in cirrhotic rats. METHODS Dimethylnitrosamine (DMN) was administered intraperitoneally for 4 weeks to induce cirrhosis. The rats were divided into three groups: sham operation (CT group), splenic artery ligation (SAL group) and splenectomy (SP group). Liver functions [alanine aminotransferase (ALT) and total bilirubin (T. Bil)], plasma TGF-beta1, histopathological changes, extent of liver fibrosis (fibrotic rate) and regeneration [Ki-67 labelling index(LI)] were investigated in each group. RESULTS ALT and T. Bil levels were significantly lower in the SP group than the CT and SAL groups. TGF-beta1 levels were significantly lower in the SP group than in the CT and SAL groups. The fibrotic rate was significantly lower in the SP group than in the CT and SAL groups. The Ki-67 labelling index was significantly higher in the SP group than in the CT and SAL groups. DISCUSSION A splenectomy significantly improved liver regeneration with reduction of plasma TGF-beta1 levels compared with splenic artery ligation in DMN-treated cirrhotic rats.
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Affiliation(s)
- Akio Morinaga
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume-city, Fukuoka, Japan.
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Ogata T, Kage M. Reconsideration of splenectomy for cirrhotic patients -Tracing the history and pitfalls-. ACTA ACUST UNITED AC 2010. [DOI: 10.2957/kanzo.51.205] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Toshiro Ogata
- Department of Surgery, Kurume University School of Medicine
| | - Masayoshi Kage
- Department of Pathlogy, Kurume University School of Medicine
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