Hepatic Histology and Metabolism Following Total Pancreatectomy and Pancreaticoduodenectomy

Study Overview
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Brief Summary
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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
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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.

Official Title
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Hepatic Histology and Metabolism Following Total Pancreatectomy and

Conditions
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Total Pancreatectomy, Pancreaticoduodenectomy, Pancreatic Diabetes, Non-Alcoholic Fatty Liver Disease, Metabolic Complication, Diabetes Mellitus

Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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liver biopsy, Lipid metabolism, Glucose metabolism, Postoperative complications, Pancreatic surgery