Evaluating the Association Between Sphingolipid Metabolites and Post-hepatectomy Liver Failure

Post-hepatectomy Liver Failure Clinical Trial

Official title:

Evaluating the Association Between Sphingolipid Metabolites and Post-hepatectomy Liver Failure

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03598465
• Other study ID #: NFEC-2018-033
• Status: Recruiting
• Start date: March 5, 2019
• Est. completion date: March 1, 2024

Study information

• Verified date: December 2023
• Source: Nanfang Hospital, Southern Medical University
• Contact: Kai Wang, MD.PhD.
• Phone: 86-13710574386
• Email: kaiwang[@]smu.edu.cn
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 270
• Est. completion date: March 1, 2024
• Est. primary completion date: February 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Hepatic Insufficiency
• Liver Failure
• Post-hepatectomy Liver Failure

Locations

Country	Name	City	State
China	The first people's hospital of Foshan	Foshan	Guangdong
China	Nanfang Hospital, Southern Medical University	Guangzhou	Guangdong
China	The second people's hospital of Shenzhen	Shenzhen	Guangdong
China	The third people's hospital of Shenzhen	Shenzhen	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Nanfang Hospital, Southern Medical University

Country where clinical trial is conducted

China, 

References & Publications (1)

Rahbari NN, Garden OJ, Padbury R, Brooke-Smith M, Crawford M, Adam R, Koch M, Makuuchi M, Dematteo RP, Christophi C, Banting S, Usatoff V, Nagino M, Maddern G, Hugh TJ, Vauthey JN, Greig P, Rees M, Yokoyama Y, Fan ST, Nimura Y, Figueras J, Capussotti L, B — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Post-hepatectomy liver failure (PHLF)	Liver failure caused by hepatectomy. (Surgery,2011,149(5):713-724).	On or after postoperative day 5 of hepatectomy.

External Links

•   The definition and diagnostic criteria of post-hepatectomy liver failure were proposed by International Liver Group of Liver Surgery(ISGLS) in 2011.