- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03598465
Evaluating the Association Between Sphingolipid Metabolites and Post-hepatectomy Liver Failure
Hepatectomy is an essential treatment for various benign and malignant diseases of the liver. However, post-hepatectomy liver failure (PHLF) is still a life-threatening complication after hepatectomy. The pathophysiological mechanism of PHLF has not yet been fully elucidated, and there is still a lack of effective strategies for either prevention or therapy of PHLF.
Sphingolipids include ceramides (CER), sphingomyelins (SM), glycosphingolipids (GSL), sphingosine (SPH), and sphingosine-1-phosphate (S1P) are multi-functional lipids that regulates cell proliferation, cell survival, cell death, inflammation, tissue fibrosis, cancer cell metastasis, and invasion. Liver is a main organ for metabolizing sphingolipids, dysregulation of specific sphingolipids is associated with several liver diseases, therefore sphingolipids have been proposed to be biomarkers of liver diseases, including hepatitis, liver cancer, fatty liver diseases, and liver fibrosis. Moreover, several studies have shown CER, SPH and S1P are critical in regulating pathophysiology of liver diseases, including liver regeneration, necrosis, and inflammation. Given that PHLF causes dramatic dysregulation in biochemical metabolism in liver, the investigators hypothesize that dysregulation of sphingolipid metabolism may also occur in PHLF, and the dysregulation of specific sphingolipids may serve as a biomarker or regulator during progression and recovery of PHLF.
This project will examine the association between sphingolipid metabolism and PHLF. Levels of sphingolipid metabolites and their related enzymes in plasma and liver tissue of patients with hepatic resection will be measured by using liquid chromatograph/electrospray ionization/mass spectrometry (LC-ESI-MS/MS) and high-throughput real-time quantitative PCR. This project will facilitate us to identify specific sphingolipid metabolites as biomarker and regulator of PHLF.
Study Overview
Status
Conditions
Detailed Description
Liver resection is an effective treatment for both benign and malignant liver diseases. However, post-hepatectomy liver failure (PHLF) is still a life-threatening complication of liver resection. The pathophysiological mechanism of PHLF has not yet been fully studied, and there is still a lack of effective strategies for either prevention or therapy of PHLF. The investigation on PHLF has important clinical significance.
Sphingolipids are a group of bioactive lipids, including ceramides (CER), sphingomyelins (SM), glycosphingolipids (GSL), etc. CER are the basic structure that constitute sphingolipids. CER are composed of long-chain bases of sphingosine and different fatty acid carbon chains. CER are of various species. According to the saturation of fatty acid carbon chains, CER can be divided into saturated CER and unsaturated CER. CER can be divided into four species, including short chain (less than 6 carbon atoms), medium chain (6-12 carbon atoms), long chain (14-20 carbon atoms), and super long chain (more than 22 carbon atoms) . Pathways of CER generation include de novo synthesis, complex sphingolipid lipid degradation pathways, and salvage synthesis pathways. CER are degraded to produce sphingosine (SPH), which can be phosphorylated to produce S1P. CER and its metabolites SPH and S1P are enigmatic lipids that regulates cell survival, death, inflammation, tissue fibrosis, cancer metastasis, and cancer invasion. Hepatocytes express activities of various sphingolipid enzymes, which makes liver an important organ for sphingolipid metabolism. Emerging evidences have shown that dysregulation of sphingolipid metabolite are associated with development and progression of certain liver diseases. In animal studies, dysregulation of ceramides has been indicated in hepatocyte survival, liver injury, and liver failure. In clinical studies, dysregulation of specific ceramide species has been identified to be associated with decompensation of cirrhosis, liver fibrosis, hepatitis, hepatocellular carcinoma. In the light of these evidences, the investigators hypothesize that dysregulation of sphingolipid metabolism may be associated with PHLF.
The investigators have established a quantitative method to measure different types of sphingolipids in human plasma, tissues, and cells using liquid chromatograph/electrospray ionization/mass spectrometry (LC-ESI-MS/MS), including C12-CER, C16-CER, C18-CER, C18:1-CER, C20-CER, C22-CER, C24-CER, C24:1-CER, SPH, S1P, C12-SM, C12-LacCER, C12-GluCER. In order to examine the correlation between sphingolipid metabolism and PHLF, the investigators will collect plasma of patients during peri-operation period of hepatectomy, after lipid extraction, the levels of sphingolipids will be measured by LC-ESI-MS/MS technology. Moreover, expression of sphingolipid-metabolizing enzymes in liver issues will be determined using high-throughput real-time quantitative PCR. The diagnostic criteria and grading of PHLF will be performed following criteria of International Liver Group of Liver Surgery. In the end, the investigators will analyze the correlation between sphingolipid metabolites and PHLF. This project will facilitate us to identify specific sphingolipid metabolites as biomarker and regulator of PHLF, and shed the light on the study of PHLF prevention and therapy.
Study Type
Enrollment (Estimated)
Contacts and Locations
Study Contact
- Name: Kai Wang, MD.PhD.
- Phone Number: 86-13710574386
- Email: kaiwang@smu.edu.cn
Study Contact Backup
- Name: Jie Zhou, MD.
- Phone Number: 86-13802973798
- Email: jacky@smu.edu.cn
Study Locations
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Guangdong
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Foshan, Guangdong, China, 528300
- Recruiting
- The First People's Hospital of Foshan
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Contact:
- Jieyuan Li, MD.PhD
- Phone Number: 86-18038861029
- Email: highlight_feeling@163.com
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Guangzhou, Guangdong, China, 510515
- Recruiting
- Nanfang Hospital, Southern Medical University
-
Contact:
- Kai Wang, MD.PhD.
- Phone Number: 86-13710574386
- Email: kaiwang@smu.edu.cn
-
Contact:
- Jie Zhou, MD.
- Phone Number: 86-13802973798
- Email: jacky@smu.edu.cn
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Shenzhen, Guangdong, China, 518035
- Recruiting
- The second people's Hospital of Shenzhen
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Contact:
- Xuesong Deng, MD,PhD
- Phone Number: 86-13528813357
- Email: 597664497@qq.com
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Shenzhen, Guangdong, China, 518112
- Recruiting
- The Third People's Hospital of Shenzhen
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Contact:
- Pengxiang Huang, MD
- Phone Number: 86-13713843030
- Email: pxhuang1995@163.com
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Sampling Method
Study Population
Description
Inclusion Criteria:
- Patients accepts hepatectomy
- In case of liver cancer, patient should received radical resection of R0 standards.
Exclusion criteria:
- Liver cancer invaded portal vein, common hepatic duct, hepatic vein trunk and/or inferior vena cava. Or the presence of extrahepatic metastases.
- Biliary obstruction, or surgery with exploration and reconstruction of bile duct.
- Surgery with splenectomy or splenic artery ligation.
- Patients with significant heart, lung, kidney and other organs of major diseases before surgery.
- The patients died in 90 days after surgery except for PHLF.
Study Plan
How is the study designed?
Design Details
Cohorts and Interventions
Group / Cohort |
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PHLF Group
The investigators will define PHLF as a postoperatively acquired deterioration in synthetic, excretory, and detoxifying functions of liver.
According to the PHLF definition and grading criteria established by International Liver Group of Liver Surgery (ISGLS) in 2011 (Surgery,2011,149(5):713-724), PHLF will be diagnosed by an increased PT-INR and concomitant hyperbilirubinemia on or after postoperative day 5.
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Non-PHLF Group
Non-PHLF will be defined as normal liver function in terms of normal PT-INR and bilirubin levels after hepatectomy on or after postoperative day 5.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Post-hepatectomy liver failure (PHLF)
Time Frame: On or after postoperative day 5 of hepatectomy.
|
Liver failure caused by hepatectomy.
(Surgery,2011,149(5):713-724).
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On or after postoperative day 5 of hepatectomy.
|
Collaborators and Investigators
Investigators
- Study Director: Jie Zhou, MD., Nanfang Hospital, Southern Medical University
- Principal Investigator: Kai Wang, MD.PhD., Nanfang Hospital, Southern Medical University
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- NFEC-2018-033
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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