Hepatic Histology and Metabolism Following Total Pancreatectomy and Pancreaticoduodenectomy

Sponsor

Steno Diabetes Center Copenhagen (Other)

Overall Status

Enrolling by invitation

CT.gov ID

NCT03864744

Collaborator

Rigshospitalet, Denmark (Other), University of Copenhagen (Other), Herlev and Gentofte Hospital (Other)

Enrollment

Location

Anticipated Duration (Months)

0.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The objective of the study is to investigate the development of NAFLD following total pancreatectomy and pancreaticoduodenectomy and to explore the histological and metabolic changes following the procedures.

Condition or Disease	Intervention/Treatment	Phase
Total Pancreatectomy Pancreaticoduodenectomy Pancreatic Diabetes Non-Alcoholic Fatty Liver Disease Metabolic Complication Diabetes Mellitus

Detailed Description

After total pancreatectomy patients are treated with exogenous insulin and pancreatic enzyme supplementation in order to treat the endocrine and exocrine insufficiencies inherently occurring postoperatively. In addition to secondary diabetes and insufficient digestive capacity, totally pancreatectomised patients face a high risk of developing non-alcoholic hepatic steatosis. Under normal circumstances non-alcoholic fatty liver disease is regarded as the hepatic manifestation of metabolic syndrome and pathophysiologically related to excess energy intake and insulin resistance resulting in fat accumulation in adipose tissue as well as in the liver. Thus, the high incidence of hepatic steatosis following total pancreatectomy is surprising as patients typically are lean, peripherally insulin sensitive and properly insulinised.Interestingly, the pancreatic hormone glucagon has been implicated in lipid metabolism and recent human data from studies investigating the effect of glucagon receptor antagonism suggest that glucagon signalling may be essential for maintaining a fat-free liver. This makes the investigators speculate that the decreased glucagon levels following pancreatic surgery may play a hitherto unrecognised role in the development of hepatic steatosis after the operation.

The study will include 33 patients scheduled for pancreatectomy (total or pancreaticoduodenectomy). They will be followed for one year. A liver biopsy will be collected during the operation on all patients. After 12 months, participants will undergo magnetic resonance spectroscopy and those who have hepatic lipid content ≥2% will undergo an ultrasound-guided percutaneous liver biopsy. Furthermore, all participants will undergo a metabolic evaulation after one year.

Study Design

Study Type:

Observational

Anticipated Enrollment :

33 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Hepatic Histology and Metabolism Following Total Pancreatectomy and

Actual Study Start Date :

Jan 30, 2019

Anticipated Primary Completion Date :

Aug 30, 2022

Anticipated Study Completion Date :

Aug 30, 2022

Outcome Measures

Primary Outcome Measures

Change in hepatic lipid content (steatosis) after total pancreatektomy or pancreaticoduodenectomy [Baseline and after 12 months.]
Evaluated by light microscopy of the liver biopsy

Secondary Outcome Measures

Hepatic lipid content [After 12 months]
Evaluated by magnetic resonance spectroscopy
Diagnosis and grade of steatohepatitis (steatosis, ballooning and lobular inflammation) [Baseline and after 12 months.]
Evaluated by light microscopy of the liver biopsy
Fibrosis stage (Kleiner classification) [Baseline and after 12 months.]
Evaluated by light microscopy of the liver biopsy
NAFLD activity score (NAS) [Baseline and after 12 months.]
Evaluated by light microscopy of the liver biopsy
Liver steatosis [After 12 months.]
Measured by controlled attenuation parametre (Fibroscan) in decibel per meter (dB/m)
Liver stiffness [After 12 months]
Measured by transcient elastrography (Fibroscan) in kilopascals (kPa)
Pancreatic endocrine dysfunction [After 12 months]
defined by HbA1c ≥ 6.5% and/or need for diabetes therapy
Alpha- and beta cell function [After 12 months]
measured by arginine stimulation test
Pancreatic exocrine dysfunction [After 12 months]
defined by f-elastase < 100 μg/g
Blood markers of liver function [Baseline and after 12 months]
including alanine transaminase (ALAT), aspartate aminotransferase (ASAT), gamma-glutamyltransferase (GGT), alkaline phosphatase, lactate dehydrogenase and bilirubin
Blood markers of glucose metabolism [Baseline and after 12 months]
HbA1c
Blood markers of glucose metabolism [Baseline and after 12 months]
Insulin
Blood markers of glucose metabolism [Baseline and after 12 months]
C-peptide
Blood markers of glucose metabolism [Baseline and after 12 months]
Glucagon
Blood markers of lipid metabolism [Baseline and after 12 months]
including lipid profiling
Blood markers of protein metabolism [Baseline and after 12 months]
including fractionated amino acids
Blood markers of nutritional status [Baseline and after 12 months]
including vitamin E and D, trace elements, lymphocytes and albumin
Blood markers related to bile-acid metabolism [Baseline and after 12 months]
including complement 4 (C4) and fibroblast growth factor 19 (FGF-19)
Changes in NAFLD/NASH biomarkers [Baseline and after 12 months]
including FGF-21

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 79 Years

Sexes Eligible for Study:

All

Inclusion Criteria:

Subject scheduled for total pancreatectomy or pancreaticoduodenectomy
Informed consent signed prior to any study-related procedure

Exclusion Criteria:

Known liver disease before total pancreatectomy or pancreaticoduodenectomy (excluding NAFLD)
Severe co-morbid disease (besides from the indication for the pancreas surgery)
Pregnancy
Any condition that the investigator feels would interfere with the safety of the trial participation or the safety of the subject
Metastatic disease

Percutaneous liver biopsy exclusion criteria (to be evaluated before last visit)