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Editor,—We read with great interest the article by Ectors et al(Gut1997;41:263–8) in which the authors describe a particular form of chronic pancreatitis in patients without chronic alcohol intake. The authors suggest the term “non-alcoholic duct destructive chronic pancreatitis” for this type of pancreatic disease in order to stress: (1) the absence of any history of alcohol abuse; (2) the target of the chronic immunological reaction; and (3) the destructive nature of the process. Characteristically some of these cases were associated with an autoimmune disease, such as primary sclerosing cholangitis, ulcerative colitis, Crohn’s disease, or Sjögren’s syndrome. The authors conclude that the inflammatory changes in the pancreatic ducts observed in this particular form of chronic pancreatitis are suggestive of an autoimmune process.
A few years ago our group postulated a new hypothesis for the pathogenesis of a particular form of chronic pancreatitis, which we defined as “primary chronic pancreatitis”.1 We suggested that the key step in the pathogenesis of this type of chronic pancreatitis may be an immune reaction against a pancreatic target antigen in the epithelium of the pancreatic ducts, with secondary inflammatory infiltration (mainly by T lymphocytes) around the main and/or secondary pancreatic ducts followed by an obliterating periductal fibrosis. This immune mediated hypothesis was based on clinical associations between chronic pancreatitis and autoimmune diseases,2 in view of the histological and radiological analogies between chronic pancreatitis and primary sclerosing cholangitis.
Other studies have since confirmed our hypothesis. Kino-Ohsaki and colleagues3 demonstrated the presence in patients with chronic pancreatitis of antibodies to carbonic anhydrase I and II, an enzyme present in the epithelium of the pancreatic and biliary ducts and the gastrointestinal tract.4 Later, Puig-Divì and coworkers5 reproduced morphological pancreatic changes mimicking the features of human chronic pancreatitis in a new experimental model obtained without ligation of the main pancreatic duct and involving an immune mechanism. In particular, in this animal model of chronic pancreatitis, the disease was induced in rats by instillation of trinitrobenzene sulphonic acid (TNBS) into the pancreatic ducts. This substance is capable of coupling membrane proteins, of modifying the structure of the epithelial surface of the pancreatic ducts and, therefore, of inducing an immune reaction to a new, previously unrecognised antigen.6 Interestingly, intracholedochal and colonic administration of TNBS in rats may induce chronic cholangitis of the small ducts7 and ulcerative colitis,8 ,9 respectively. More recently, Hunger and colleagues10 have demonstrated a preferential activation of cell mediated cytotoxicity in the pancreas of patients with alcoholic chronic pancreatitis and postulate that an immune reaction is involved in tissue destruction in this condition. By and large, these studies seem to show that chronic pancreatitis may be induced by an immune mediated mechanism and that this mechanism might explain the clinical associations between chronic pancreatitis and sclerosing diseases of the biliary tract (primary sclerosing cholangitis and primary biliary cirrhosis) or chronic inflammatory diseases of the gastrointestinal tract.
In the study by Ectors et al the pancreas in non-alcoholic chronic pancreatitis was characterised by dense lymphocyte infiltrates (mainly T lymphocytes) around the interlobular ducts with a patchy distribution. These changes, which are quite different from those in alcoholic chronic pancreatitis, lead to a periductal obliterating fibrosis and, later, to replacement of acinar parenchyma with fibrous tissue upstream of the ductal stenosis. In our opinion, the “non-alcoholic destructive chronic pancreatitis” suggested by Ectors et al probably represents a severe form of “primary chronic pancreatitis”. Their study, in fact, presents a selection bias: the authors examined pancreatic specimens obtained from patients treated by resection because of such severe inflammation of the pancreas involving the biliary tract, that carcinoma of the head of the pancreas was clinically suspected. However, the clinical expression of “primary chronic pancreatitis” is probably more heterogeneous and we believe that many patients with the classic symptoms of chronic pancreatitis and a mild-to-moderate form of “primary chronic pancreatitis” may be misdiagnosed in the absence of histological findings. Moreover, we wish to stress that it is incorrect to divide chronic pancreatitis into alcoholic and non-alcoholic forms and to postulate that an immune mediated mechanism is present only in idiopathic chronic pancreatitis. Alcohol abuse, like cigarette smoking, may produce structural alterations in the membranes of the pancreatic duct epithelium, directly or indirectly via the production of acetylaldehyde, and trigger an immunological response in genetically predisposed subjects. In our clinical series, calcifications were present in four (57%) of seven patients with chronic pancreatitis and ulcerative colitis,11 and in seven (78%) of nine patients with chronic pancreatitis and chronic sialodenitis.12 In all of these patients with chronic pancreatitis, autoimmune diseases and pancreatic calcifications we documented chronic alcohol intake and/or cigarette smoking. The absence of protein plugs and intraductal calcifications shown by Ectors et al in non-alcoholic chronic pancreatitis probably reflects the incorrect inclusion criteria.
In clinical practice, we therefore prefer to divide patients with chronic pancreatitis into those with “primary chronic pancreatitis” (immune mediated disease) and those with “secondary chronic pancreatitis” (obstructive disease). If this simple classification is accepted, the future clinical challenge will be to identify reliable criteria for diagnosing primary or secondary chronic pancreatitis.