Genetic Risk Factors for Pancreatic Disorders David C. Whitcomb  Gastroenterology  Volume 144, Issue 6, Pages 1292-1302 (May 2013) DOI: 10.1053/j.gastro.2013.01.069 Copyright © 2013 AGA Institute Terms and Conditions

Figure 1 Progression of pancreatic injury. CP is illustrated as a syndrome that develops over time (left to right). (A) Individuals may live for years with multiple susceptibility factors. Patients at very high risk may be candidates for prevention strategies, such as avoiding alcohol. (B) When a stochastic event leads to pancreatic injury, it initiates the Sentinel Acute Pancreatitis Event (SAPE) with intrapancreatic immune system activation. Management includes identification of actionable risk and prevention of RAP. (C) Factors such as alcohol, smoking, and genetic mutations or presently unidentified factors affect the specialized cells of the pancreas and infiltrating cells to cause various complications. Research efforts are focusing on identifying risk, mechanisms, and biomarkers of the progression pathways. Gastroenterology 2013 144, 1292-1302DOI: (10.1053/j.gastro.2013.01.069) Copyright © 2013 AGA Institute Terms and Conditions

Figure 2 Genetic and environmental factors that affect acinar cells or ducts. Premature trypsin activation may occur in the acinar cell or in the duct to initiate pancreatitis. The majority of known risk factors can be classified as primarily affecting the acinar cells or pancreatic ducts. Understanding the site of likely trypsin activation and mechanism may guide preventative strategies in the future. IPMN, intraductal papillary mucinous neoplasm. Reprinted with permission from Solomon and Whitcomb.76 Gastroenterology 2013 144, 1292-1302DOI: (10.1053/j.gastro.2013.01.069) Copyright © 2013 AGA Institute Terms and Conditions

Figure 3 Risks of RAP and CP. Data collected in population-based analysis of 7456 residents of Allegheny County, Pennsylvania, following their first (sentinel) episode of AP. (A) Risk of developing RAP based on etiology. (B) Risk of CP based on the presence or absence of documented RAP. Reprinted with permission from Yadav et al.84 Gastroenterology 2013 144, 1292-1302DOI: (10.1053/j.gastro.2013.01.069) Copyright © 2013 AGA Institute Terms and Conditions

Figure 4 Factors contributing to the development of pancreatitis. The first hit increases susceptibility to injury, whereas the second hit affects the immune response (and includes leukocytes, such as M2 macrophages) to promote stellate cell–associated fibrosis. Alcohol could injure the pancreas via its effects on acinar cells, but it is probably more important in the second group as a modifier of the immune response. For example, it could promote a Th17-cell response or act directly on stellate cells (dashed lines). Altered trypsin functions in acinar cells or ducts could also initiate disease. In either case, similar second hit factors then contribute to the development of fibrosis (via variants in SPINK1 and/or CTRC). Severe AP involves widespread pancreatic necrosis (approximately 90% of tissue), which leads directly to scarring and fibrosis in the recovery phase. Obese patients could have areas of adipose tissue that contain local necrosis of acinar tissue, which has been linked to lipotoxicity. Progressive fibrosis could occur in patients with RAP. Other pathways include AIP, in which the pathway to fibrosis is less well understood. Gastroenterology 2013 144, 1292-1302DOI: (10.1053/j.gastro.2013.01.069) Copyright © 2013 AGA Institute Terms and Conditions

David C. Whitcomb Gastroenterology 2013 144, 1292-1302DOI: (10.1053/j.gastro.2013.01.069) Copyright © 2013 AGA Institute Terms and Conditions