As many as 40% of individuals with chronic pancreatitis have no recognizable predisposing factors. As with acute pancreatitis, however, a growing number of these “idiopathic” cases are associated with inherited mutations in genes, such as CFTR, that are important for normal pancreatic exocrine function. Recent studies have also identified polymorphisms in genes encoding exocrine pancreatic enzymes, including carboxypeptidase A1 (CPA1) and lipase (CEL), that may confer increased susceptibility to chronic pancreatitis.
Although the pathogenesis of chronic pancreatitis is not well defined, several hypotheses are proposed:
Ductal obstruction by concretions. Many of the inciting agents in chronic pancreatitis (e.g., alcohol) increase the protein concentration of pancreatic secretions, and these proteins can form ductal plugs.
Toxic-metabolic. Toxins, including alcohol and its metabolites, can exert a direct toxic effect on acinar cells, leading to lipid accumulation, acinar cell loss, and eventually parenchymal fibrosis.
Oxidative stress. Alcohol-induced oxidative stress may generate free radicals in acinar cells, leading to membrane damage (Chapter 2), and subsequent expression of chemokines like interleukin-8 (IL-8), which recruits inflammatory cells. Oxidative stress also promotes the fusion of lysosomes and zymogen granules with resulting acinar cell necrosis, inflammation, and fibrosis.
Inappropriate activation of pancreatic enzymes due to mutations affecting genes mentioned earlier.
In contrast to acute pancreatitis, a variety of profibrogenic cytokines, such as transforming growth factor-β (TGF-β), connective tissue growth factor, and platelet-derived growth factor, are secreted in chronic pancreatitis by infiltrating immune cells such as macrophages. These cytokines induce the activation and proliferation of periacinar myofibroblasts (“pancreatic stellate cells”), which deposit collagen and give rise to fibrosis.
MORPHOLOGYChronicpancreatitisischaracterizedbyparenchymal fibrosis, reduced number and size of acini, and variable dilation of the pancreatic ducts; thereisarelativesparingoftheisletsofLangerhansinitially(
Fig.17.4A ).Acinar loss isaconstantfeature,usuallywithachronicinflammatoryinfiltratearoundremaininglobulesandducts.Theductalepitheliummaybeatrophiedorhyperplasticorexhibitsquamousmetaplasia,andductalconcretionsmaybenoted(
Fig.17.4B ).TheremainingisletsofLangerhansbecomeembeddedinthesclerotictissueandmayfuseandappearenlarged;eventuallytheyalsodisappear.Ongrossevaluation,theglandishard,sometimeswithextremelydilatedductsandvisiblecalcifiedconcretions.
Autoimmunepancreatitis(AIP)isadistinctformofchronicpancreatitisthatischaracterizedbystrikinginfiltrationofthepancreasbylymphocytesandplasmacells,manyofwhicharepositiveforIgG4,accompaniedbya“swirling”fibrosisandvenulitis(lymphoplasmacytic sclerosing pancreatitis).
Chronic pancreatitis manifests as repeated bouts of jaundice, vague indigestion, or persistent or recurrent abdominal and back pain, or it may be entirely silent until pancreatic insufficiency and diabetes mellitus develop (the latter as a consequence of islet destruction). Attacks can be precipitated by alcohol abuse, overeating (which increases demand on pancreatic secretions), or opiates or other drugs that increase the muscle tone of the sphincter of Oddi.
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