Chronic pancreatitis is a progressive inflammatory disorder in which pancreatic secretory parenchyma is destroyed and replaced by fibrous tissue, eventually leading to malnutrition and diabetes. Pancreatitis is usually classified into two forms—acute and chronic. Acute pancreatitis is characterised by acute necroinflammation of the pancreas and peripancreatic tissues with, in most instances, complete recovery of pancreatic structure and function once the inflammation resolves. Chronic pancreatitis, on the other hand, is characterised by irreversible destruction of pancreatic structure with progressive loss of both exocrine and endocrine function. Two forms are recognised—a large-duct calcifying type and a small-duct variant. The main symptom of chronic pancreatitis is usually pain, which occurs as attacks that mimic acute pancreatitis or as constant and disabling pain. Repeated episodes of acute pancreatitis can lead to increasing residual damage to the gland, eventually resulting in the changes of chronic pancreatitis—that is, acinar atrophy and fibrosis (the necrosis-fibrosis sequence).
In normal pancreas, quiescent pancreatic stellate cells (PSCs), the principal effector cells in liver fibrosis, can be identified by staining for the cytoskeletal protein desmin, a stellate cell selective marker. PSCs are found in a periacinar location, with long cytoplasmic processes encircling the base of pancreatic acini. In vitro studies with cultured PSCs have revealed that the cells store vitamin A in the form of lipid droplets in the cytoplasm, a feature similar to that described for hepatic stellate cells. During pancreatic injury, PSCs are activated—that is, they proliferate, transform into a myofibroblastic phenotype, which exhibits positive staining for the cytoskeletal protein α smooth muscle actin (α-SMA), and synthesise and secrete increased amounts of extracellular matrix proteins, particularly collagen. A burst of reactive oxygen species (ROS) is the trigger of so-called pancreastasis and as the potentiator of inflammation by activating signaling cascades that convert the damaged acinar cell into a factory for chemokines and cytokines. ROS serve several physiological roles, including in signal transduction, but an excess of ROS compared with antioxidant capacity (electrophilic stress) is potentially very damaging.
Alcohol has long been regarded as the leading cause of chronic pancreatitis in Europe, the USA, Brazil, Mexico, and South Africa, and is now regarded as the main cause of the disease also in Australia and South Korea. Although the pancreas processes ethanol efficiently (via a non-oxidative route that produces fatty acid ethyl esters, and by oxidation via the acetaldehyde pathway), its metabolites injure acinar cells and activate stellate cells in vitro. In animal models, small doses of ethanol induce CYP2E1, thus increasing the toxicity from other chemicals to which the animal is simultaneously exposed. Moreover, CYP2E1 is the main pathway that metabolises ethanol upon chronic excessive ingestion, but this pathway releases ROS.