The annual incidence of acute pancreatitis ranges from 13 to 45 per 100,000 population and has increased since 1990. A majority of cases of acute pancreatitis are related to biliary tract disease (45%) (a passed gallstone, usually 5 mm or less in diameter) or heavy alcohol intake (20%), with worldwide variations. The exact pathogenesis is not known but may include edema or obstruction of the ampulla of Vater, reflux of bile into pancreatic ducts, and direct injury of pancreatic acinar cells by prematurely activated pancreatic enzymes (eFigure 16–58). Among the numerous other causes or associations are (1) hyperlipidemias (chylomicronemia, hypertriglyceridemia, or both); (2) hypercalcemia; (3) abdominal trauma (including surgery); (4) medications (including azathioprine, mercaptopurine, asparaginase, pentamidine, didanosine, valproic acid, tetracyclines, dapsone, isoniazid, metronidazole, estrogen and tamoxifen [by raising serum triglycerides], sulfonamides, mesalamine, celecoxib, sulindac, leflunomide, thiazides, simvastatin, fenofibrate, enalapril, methyldopa, procainamide, sitagliptin, exenatide, possibly corticosteroids, and others); (5) vasculitis; (6) infections (eg, mumps, cytomegalovirus, HEV, M avium intracellulare complex, SARS-CoV-2); (7) peritoneal dialysis; (8) cardiopulmonary bypass, single- or double-balloon enteroscopy; and (9) ERCP. Medication-induced acute pancreatitis is generally dose-related and associated with worse outcomes than that due to other causes. In patients with pancreas divisum, a congenital anomaly in which the dorsal and ventral pancreatic ducts fail to fuse, acute pancreatitis may result from stenosis of the minor papilla with obstruction to flow from the accessory pancreatic duct, although concomitant genetic mutations, particularly in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, may actually account for acute pancreatitis in these patients. Genetic mutations also predispose to chronic pancreatitis, particularly in persons younger than 30 years of age if no other cause is evident and a family history of pancreatic disease is present (see Chronic Pancreatitis). Acute pancreatitis may also result from an anomalous junction of the pancreaticobiliary duct (pancreaticobiliary malunion). Rarely, acute pancreatitis may be the presenting manifestation of a pancreatic or ampullary neoplasm. Celiac disease appears to be associated with an increased risk of acute and chronic pancreatitis. Apparently “idiopathic” acute pancreatitis is often caused by occult biliary microlithiasis but unlikely to be caused by sphincter of Oddi dysfunction involving the pancreatic duct. Between 15% and 25% of cases are truly idiopathic. Smoking, high dietary glycemic load, and abdominal adiposity increase the risk of pancreatitis, and older age and obesity increase the risk of a severe course; vegetable consumption, dietary fiber, and use of statins may reduce the risk of pancreatitis, and coffee drinking may reduce the risk of nonbiliary pancreatitis.