Pathogenetics of chronic pancreatitis

Chronic pancreatitis is a condition that is associated with the progressive inflammation of the pancreas which over time gives rise to irreversible morphological changes accompanied by impairment of both exocrine and endocrine functions (Majumder and Chari 2016). Over the last 20 years, molecular genetics has played an increasingly important role in elucidating the aetiology of chronic pancreatitis. The dawn of the new era in the genetic analysis of autosomal dominant hereditary pancreatitis (OMIM #167800) was heralded by the mapping of a disease locus to the long arm of chromosome 7 (Le Bodic et al. 1996; Pandya et al. 1996; Whitcomb et al. 1996b) and the subsequent identification of a gain-of-function missense mutation (i.e., p.Arg122His) in the cationic trypsinogen gene (PRSS1; OMIM #276000) (Whitcomb et al. 1996a). Thereafter, a steady stream of chronic pancreatitis susceptibility (or protective) variants in different genes has been reported. The analysis of variants in four specific genes, all highly expressed in human pancreatic acinar cells [PRSS1, PRSS2 (encoding anionic trypsinogen; OMIM #601564), SPINK1 (encoding pancreatic secretory trypsin inhibitor; OMIM #167790) and CTRC (encoding chymotrypsin C, which specifically degrades all human trypsinogen/trypsin isoforms (OMIM #601405) (Szmola and Sahin-Tóth 2007))] has firmly established the importance of a homeostatic balance between the activation and inactivation of trypsinogen within the pancreas, thereby defining a trypsin-dependent pathway in the pathogenesis of chronic pancreatitis. Whereas gain-of-function missense mutations and copy number variants in PRSS1 (Le Maréchal et al. 2006; Whitcomb et al. 1996a) and loss-of-function variants in SPINK1 (Witt et al. 2000) and CTRC (Masson et al. 2008b; Rosendahl et al. 2008) predispose to chronic pancreatitis, loss-of-function variants in PRSS1 (Boulling et al. 2015; Chen et al. 2003; Derikx et al. 2015; Whitcomb et al. 2012) and PRSS2 (Witt et al. 2006) protect against the disease