Genetic Testing for Hereditary Pancreatitis: Guidelines for Indications, Counselling, Consent and Privacy Issues

The European Pancreatic Club Lifetime Achievement award is a distinction awarded for research on the pancreas. It comes with the obligation to submit a review article to the society's journal, Pancreatology. Since the research topics of my group have recently been covered in reviews and book chapters I want to use this opportunity to appraise the stations of my clinical and research education, the projects that I pursued and abandoned, the lessons I have learned from them, and the women and men who influenced my training and development as a physician scientist. Some crossed my path, some become collaborators and friends, and some turned into role models and had a lasting impact on my life.

Pancreatitis is characterized as self-digestion of the pancreas by its own proteases. A premature activation of digestive enzymes within pancreatic acinar cells results in necrotic cell death and the activation of the immune system. The serine protease trypsinogen is suggested to play a crucial role in this process. Trypsinogen is activated by the lysosomal hydrolase cathepsin B within the acinar cell and defines the onset of disease. This event is accompanied by a local and systemic immune response. The significant role of trypsinogen is underlined by genetic data; different mutations within PRSS1, the cationic trypsinogen, or other genes that are related to the activation, degradation, or inhibition of trypsin are associated with an increased risk of chronic pancreatitis.

Acute pancreatitis is currently the most common cause of hospital admission among all nonmalignant gastrointestinal diseases. To understand the pathophysiology of the disease and as a potential step toward developing targeted therapies, attempts to induce the disease experimentally began more than 100 years ago. Recent decades have seen progress in developing new experimental pancreatitis models as well as elucidating many underlying cell biological and pathophysiological disease mechanisms. Some models have been developed to reflect specific causes of acute pancreatitis in human beings. However, the paucity of data relating to the molecular mechanisms of human disease, the likelihood that multiple genetic and environmental factors affect the risk of disease development and its severity, and the limited information regarding the natural history of disease in human beings make it difficult to evaluate the value of disease models. Here, we provide an overview of key models and discuss our views on their strengths for characterizing cell biological disease mechanisms or for identifying potential therapeutic targets. We also acknowledge their limitations.

Acute pancreatitis is a common gastrointestinal disorder burdened with a high mortality. Two pathophysiological events during experimental pancreatitis are thought to determine the clinical course: premature digestive protease activation and tissue infiltration by inflammatory cells. We have investigated the effect of AZD8309, a potent and orally bioavailable antagonist of the chemokine receptor CXCR2, which has been proposed to regulate the transmigration of neutrophils.

Male C57BL6 mice (25–30 g) received gavage feeding of AZD8309 (50 mg/kg/BW) or mannitol (controls) twice daily starting 3 h prior to pancreatitis induction. Mild pancreatitis was induced by i.p. caerulein administration (50 μg/kg BW), severe pancreatitis by intraductal taurocholate (2%). Pancreas, lung, and serum was harvested up to 48 h after pancreatitis induction and used for histopathology, amylase, lipase, cathepsin B, trypsin, and elastase activity measurements, myeloperoxidase (MPO) content and cytokine concentrations.

Oral administration of AZD8309 significantly reduced MPO in the pancreas and lungs (8 h & 24 h) and reduced intrapancreatic trypsin and elastase activity (8 h) in caerulein-pancreatitis. In taurocholate-pancreatitis AZD8309 reduced cathepsin B activity and MPO. Serum cytokine levels were reduced by AZD8309 as well as histopathological damage.

The CXCR2 antagonist AZD8309 reduced the transmigration of neutrophils as well as intrapancreatic protease activation in experimental pancreatitis. This effect was sufficient to reduce the overall severity of the disease. CXCR2 may therefore be a viable therapeutic target and AZD8309 a suitable agent for the treatment of acute pancreatitis.