Value of genetic testing in the management of pancreatitis
Authors: D C Whitcomb
Journal: Gut (2004)

The majority of pancreatic diseases are associated with genetic polymorphisms.Recent breakthroughs in understanding the origin and pathways toward pancreatic diseases, and especially acute and chronic pancreatitis, reveal that specific variation in the genomic DNA sequence of individuals strongly influence their susceptibility to pancreatitis, the severity and nature of the inflammatory process, and the likelihood of various complications.Acute pancreatitis is an event, and chronic pancreatitis is a process.They are sequentially linked with chronic pancreatitis reflecting a pathophysiological response to acute pancreatitis events.The triggers, thresholds, mechanism of injury, and immunological responses of individuals with acute and chronic pancreatitis are being organised and defined.In the future, early use of genetic testing will likely play a critical role in early diagnosis and prognosis of pancreatic diseases, and could guide new and effective preventative and therapeutic interventions.The benefits and risk of limited genetic testing have been defined by consensus conference, while the framework for future and more extensive genetic evaluation is still developing.Diseases of the pancreas continue to be among the most mysterious and difficult of all human diseases to study.The pancreas is inaccessible to physical examination because of its retroperitoneal location, and remains invisible to standard radiographic examination because it lacks bony structure.Biopsies are also rarely done for fear of triggering acute pancreatitis, creating fistula, or initiating bleeding.These factors limited our understanding of pancreatic physiology and pathophysiology, limited early diagnosis, and precluded development of effective treatment for all major pancreatic diseases, until now.Growing evidence suggests that most diseases of the pancreas have genetic predispositions and/ or basis.This should not be surprising as the pancreas is an organ shielded from direct exposure to a hostile environment (unlike the skin, lungs, and digestive tract), and neither filters nor detoxifies most noxious agents (unlike the kidney and liver).As a result, environmental factors appeared to play a limited role in pancreatic diseases.Thus understanding pancreatic disease has lagged behind advances in other diseases until new genetic methods became available.The latest evidence demonstrates that idiopathic and alcoholic acute pancreatitis, and especially the various forms of chronic pancreatitis, are most often complex disorders that occur in individuals having multiple risk factors for susceptibility and severity that together contribute to the aetiology through pathological pathways that are activated by triggering factors.Understanding these interactions will provide the rationale for future evaluation and treatment.We are now on the verge of a new era in testing and treating diseases of the pancreas.But to understand the timing, purpose, and value of genetic testing, one must understand the clinical and pathophysiological context.This includes the origin, aetiologies, and processes leading to acute and chronic pancreatitis, and the genetic alterations known to contribute to these disorders.This framework should also be useful for categorising and applying new mutations to our understanding of pancreatic diseases.The major issues associated with genetic testing will be discussed from this context.The current knowledge provides genetic insight into acute pancreatitis, with the understanding that recurrent pancreatitis, in some cases, leads to chronic pancreatitis.In our view, chronic pancreatitis requires three ''hits'', which can include environmental stressors, pancreatic injury from trypsinogen activation, and an inappropriate immunological response leading to chronic inflammation and/or fibrosis.Specific genetic testing in the future should predict who will have recurrent acute pancreatitis and who will progress to chronic pancreatitis.Genetic testing is one of the most important and powerful tools ever developed.When properly performed, results are 100% sensitive and specific for the detection of specific DNA sequence 1710 www.gutjnl.