Acute Pancreatitis Targets (APT) Study
Acute Pancreatitis Targets (APT) Study
The severity of acute pancreatitis varies considerably from minor symptoms to multi-organ
 failure. The pathophysiological mechanisms associated with these individual differences in
 severity are largely unknown. Acute pancreatitis is therefore classified based on clinical
 characteristics and routine blood samples. Information about pathophysiology and molecular
 subtypes of acute pancreatitis is needed to develop specific biomarkers and identify new drug
 targets. The investigators therefore plan to undertake an explorative study, which includes
 state-of-the-art biochemical assessment of patients with acute pancreatitis including
 multi-OMICS focusing on transcriptomics and proteomics.
Introduction Acute pancreatitis is a sudden inflammation of the pancreas with clinical
 manifestations ranging from a mild self-limiting disease to a severe form with necrosis of
 the pancreas and multi-organ dysfunction. Population-based cohort studies report a global
 incidence of 23 to 49 cases per 100,000 per year. In Denmark, more than 4,000 patients are
 admitted with acute pancreatitis each year. Gallstones and alcohol account for approximately
 80% of all cases. Although the clinical characteristics and induction mechanism differ in the
 two groups, no differences in the inflammatory profile have been identified.

 Acute pancreatitis is characterised by an early phase 7-10 days after the onset and a late
 phase after more than 10-14 days. The early phase is dominated by the host response to the
 local pancreatic injury leading to systemic inflammation. The late phase is characterized by
 infected pancreatic or peri-pancreatic necrosis, systemic signs of infection, and possible
 local complications including splanchnic vein thrombosis. Multi-organ dysfunction may occur
 in the early as well as the late phase. Although supportive treatment and minimally invasive
 techniques have improved the overall prognosis, the mortality among patients with severe
 pancreatitis remains about 10 to 15%. Once persistent multi-organ dysfunction develops,
 mortality is as high as 30 to 40%.

 Following an episode of acute pancreatitis patients are in risk of developing comorbidities.
 Fifteen percent of the patients will develop diabetes within a year and 10 % will develop
 chronic pancreatitis after a first episode of acute pancreatitis.

 At present time, there are no specific treaments to prevent attacks of acute pancreatitis,
 nor there are any disease modifying measures. Patients are mainly treated with supportive
 care which includes close monitoring of organ functions, pain management, fluid resuscitation
 and nutrition.

 Several prognostics scores have been developed to identify patients at risk of developing
 severe acute pancreatitis. The scores are used in patient triage. Most scores include age and
 an assessment of the respiratory, circulatory and renal function. Blood glucose, platelets,
 albumin and calcium are used as markers of third space fluid losses, inflammation,
 lipolysis/fat necrosis and impaired pancreatic endocrine function. Other clinical variables
 include obesity, body mass index (BMI) and abdominal fat.

 Genetic polymorphisms in the tumour necrosis factor (TNF)-alfa and the Monocyte
 chemoattractant protein (MCP)-1 genes are associated with an increased risk of acute
 pancreatitis, but none are currently used in clinical practice.

 Pancreatic enzymes Activation of the pancreatic enzymes: amylase, lipases (including
 pancreatic lipase, phospholipase and sterol esterase) and proteases (including trypsin,
 chymotrypsin, carboxypeptidase and elastases) play a key role in the development of acute
 pancreatitis. Elevated amylase and lipase are used in the diagnosis, but cannot predict
 disease severity.

 Trypsin and elastase levels are elevated for a longer time than amylase and lipase along with
 their potential catalysing effects on proteins.

 Locally, activated enzymes are responsible for the development of pancreatic and
 peripancreatic necrosis, but little is known about the effect of the circulating enzymes.
 Theoretically, the enzymes can catalyse degradation of carbohydrates, lipids and protein
 throughout the body causing systemic metabolic alterations and contribute to disease severity
 and progression.

 Endocrine function Acute pancreatitis is associated with extensive metabolic changes, which
 occur from the early stage. Elevated plasma glucose is used as a predictor of the disease
 severity. Possibly hyperglycaemia worsens the outcome, but also could be a marker of
 pancreatic damage and the metabolic stress related to critical illness. Hyperglycaemia on
 admission was associated with the development of pancreatic necrosis and pseudocysts and
 longer hospital stay The findings regarding hyperglycaemia organ dysfunction are equivocal.

 Patients with acute pancreatitis have increased degradation of pro, but also increased
 proinsulin and insulin levels as well as glucagon and glucagon related peptides during the
 first days after hospital admission. The levels are fluctuating and may reflect a combination
 of a transient reduction in secretion from beta-cells and changes in the breakdown by
 activated proteases from the pancreas.

 Increased levels of cortisol during the acute inflammatory acute phase are also likely to be
 involved in the metabolic changes. The studies investigating endocrine function during acute
 pancreatitis are limited and only include few patients.

 The complex interactions between inflammatory pathways, gut hormones, obesity and endocrine
 function is impaired even after the initial stage of the inflammatory disease.

 Obesity, lipolysis and acute pancreatitis In patients with acute pancreatitis, obesity is
 associated with the risk of both local and systemic complication. Theoretically,
 obesity-associated low-grade inflammatory predisposes to the development of a systemic
 inflammatory response. Serum concentrations of interleukins and c-reactive protein (CRP) were
 increased in patients with obesity, and adiponectin levels are associated with the severity
 of acute pancreatitis. Furthermore, abdominal adiposity increases the risk of acute
 pancreatitis and is correlated with the severity, local complications and death. The
 association may reflect lipolysis in the visceral adipose tissue and the concentration of
 fatty acids is increased in pancreatic necrotic collections. Intraperitoneal administration
 of unsaturated fatty acids to rats in a model of acute pancreatitis, increased cytokine
 levels was associated with an increased risk of multi-organ dysfunction, pancreatic necrosis
 and mortality. These changes were prevented by the administration of the lipase inhibitor
 orlistat.

 Proteomics and acute pancreatitis Previous studies have assessed the identity and amount of
 proteins as well as proteolysis and post-translational modifications of proteins in acute
 pancreatitis. Animal models have found an increase in certain proteins related to stress and
 inflammation. The increase can occur through an increased synthesis as well as migration or
 decreased degradation. Similar changes are likely to occur in humans. Transcriptomic
 profiling has not been performed in acute pancreatitis. However, the method has provided
 invaluable information about inflammatory changes, potential diagnostic markers and cellular
 changes in several different diseases such as diabetes, non-alcoholic fatty liver disease and
 pancreatic cancer.

 Objective The investigators plan to elucidate the pathophysiology and molecular subtypes of
 acute pancreatitis in order to develop specific biomarkers and identify new drug targets. The
 evaluation will include an analysis of the impact of obesity and the metabolic profile during
 the disease course of acute pancreatitis.
Inclusion Criteria:

 -  Adult patients (age >18 years) with acute pancreatitis according to the revised
 Atlanta criteria;12

 -  Informed consent;

 -  Known time of debut of symptoms.

 Exclusion Criteria:

 -  Chronic pancreatitis;

 -  Pregnancy;

 -  Known malignant disease;

 -  More than 72 hours from debut of symptoms to inclusion.