Hepatic Histology and Metabolism Following Total Pancreatectomy and Pancreaticoduodenectomy

Hepatic Histology and Metabolism Following Total Pancreatectomy and

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Diabetes Mellitus; Non-Alcoholic Fatty Liver Disease; Pancreaticoduodenectomy; Metabolic Complication; Total Pancreatectomy; Pancreatic Diabetes

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 Type: Observational
• Enrollment (Anticipated): 33

Contacts and Locations

Study Locations

• Denmark
  • Hellerup, Denmark, 2900
    • Steno Diabetes Center Copenhagen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 79 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Subjects who undergo total pancreatectomy or pancreaticoduodenectomy at Rigshospitalet, Copenhagen.

Description

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)

• MR spectroscopy demonstrating lipid content <2%
• Haemoglobin <6 mmol/L
• INR >1.5
• Trombocytes <40 × 109/L
• Skin infection in area where biopsy will be sampled

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in hepatic lipid content (steatosis) after total pancreatektomy or pancreaticoduodenectomy	Evaluated by light microscopy of the liver biopsy	Baseline and after 12 months.

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Steno Diabetes Center Copenhagen
• Collaborators: Rigshospitalet, Denmark; University of Copenhagen; Herlev and Gentofte Hospital
• Investigators: Study Director: Filip Krag Knop, Professor, Steno Diabetes Center Copenhagen, Clinical metabolic physiology

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 30, 2019
• Primary Completion (ANTICIPATED): August 30, 2022
• Study Completion (ANTICIPATED): August 30, 2022

Study Registration Dates

• First Submitted: March 1, 2019
• First Submitted That Met QC Criteria: March 4, 2019
• First Posted (ACTUAL): March 6, 2019

Study Record Updates

• Last Update Posted (ACTUAL): October 4, 2021
• Last Update Submitted That Met QC Criteria: September 27, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Postoperative complications; Pancreatic surgery; liver biopsy; Lipid metabolism; Glucose metabolism
• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Liver Diseases; Diabetes Mellitus; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: H-18010755

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No