Hepatic Histology and Metabolism Following Total Pancreatectomy and Pancreaticoduodenectomy

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

• Registration Number: NCT03864744
• Lead Sponsor: Steno Diabetes Center Copenhagen

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.

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 Timeline

• Study Start: 2019-01-30
• Study First Submitted: 2019-03-01
• Study First Submitted QC: 2019-03-04
• Study First Posted: 2019-03-06
• Status Verified: 2021-09
• Last Update Submitted: 2021-09-27
• Last Update Posted: 2021-10-04
• Primary Completion: 2022-08-30
• Study Completion: 2022-08-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 33

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 & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Hepatic lipid content	After 12 months	Evaluated by magnetic resonance spectroscopy
Pancreatic exocrine dysfunction	After 12 months	defined by f-elastase \< 100 μg/g
Blood markers of glucose metabolism	Baseline and after 12 months	Glucagon
Blood markers of protein metabolism	Baseline and after 12 months	including fractionated amino acids
Liver steatosis	After 12 months.	Measured by controlled attenuation parametre (Fibroscan) in decibel per meter (dB/m)
Blood markers of lipid metabolism	Baseline and after 12 months	including lipid profiling
NAFLD activity score (NAS)	Baseline and after 12 months.	Evaluated by light microscopy of the liver biopsy
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
Changes in NAFLD/NASH biomarkers	Baseline and after 12 months	including FGF-21
Diagnosis and grade of steatohepatitis (steatosis, ballooning and lobular inflammation)	Baseline and after 12 months.	Evaluated by light microscopy of the liver biopsy
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
Blood markers of nutritional status	Baseline and after 12 months	including vitamin E and D, trace elements, lymphocytes and albumin
Fibrosis stage (Kleiner classification)	Baseline and after 12 months.	Evaluated by light microscopy of the liver biopsy
Liver stiffness	After 12 months	Measured by transcient elastrography (Fibroscan) in kilopascals (kPa)
Blood markers related to bile-acid metabolism	Baseline and after 12 months	including complement 4 (C4) and fibroblast growth factor 19 (FGF-19)

Trial Locations

Locations (1)

Steno Diabetes Center Copenhagen; 🇩🇰 Hellerup, Denmark