Granulomatous pancreatitis - granulomas in chronic pancreatitis

Summary Granulomatous pancreatitis can be described only in infectious granulomas and pancreatic involvement by systemic granulomatosis. The presence of classical chronic tryptic pancreatitis in addition to individual sarcoidosis granulomas in one of our cases of sarcoidosis, shows that pancreatitis in a patient with generalized granulomatosis should not necessarily be considered granulomatous pancreatitis. A variety of foreign-body granulomas found in the pancreas may be explained by previous surgical operations, and other foreign bodies introducted iatrogenically. Occasionally, the pancreas in chronic pancreatitis contains granulomas that must be considered foreign body granulomas, although the causal foreign body cannot be identified. We believe that we can identify inspissated secretion that has passed out of the ductal system into the interstitium as the foreign body responsible. It is not possible to establish whether such iatrogenic measures as manipulations of the duct with back-up of the secretion within the ductal system, has any causative involvement in this secretion oedema. However, the absorption of the individual parenchymal secretions is impaired to such a degree that any extravasated remain in situ for a lengthy period. The absorption of the aqueous constituents leads to inspissation, so that it can finally be absorbed only through the formation of foreign body granulomas.The same granulogenic property in highly scarred pancreatic parenchyma is also recognizable in the abnormal degradation mode of normally absorbable Ethibloc, and in the excessive arterial and periarterial reactions following angiography.The presence of granulomas within the parenchyma of the pancreas in chronic pancreatitis, many of which have been induced by endogenous and/or exogenous foreign bodies would not lead us to refer to a granulomatous pancreatitis, since the remaining sections of the parenchyma manifest typical necroses and scar foci of chronic pancreatitis. We would characterize these granulomas by the term granulomas in chronic pancreatitis, and differentiate this from granulomatous pancreatitis.Dedicated to Prof. G. Seifert on the occasion of his 65th birthday     

Increased etheno-DNA adducts in affected tissues of patients suffering from Crohn's disease, ulcerative colitis, and chronic pancreatitis

Chronic inflammatory processes induce oxidative stress and lipid peroxidation (LPO), hereby generating DNA-reactive aldehydes such as trans-4-hydroxy-2-nonenal (HNE). Etheno-modified DNA bases are inter alia generated by reaction of DNA with HNE. Using an immunoaffinity-(32)P-postlabeling method, the authors have investigated etheno-DNA adduct levels 1,N (6)-ethenodeoxyadenosine (epsilondA) and of 3,N (4)-ethenodeoxycytidine (epsilondC) in the pancreas of chronic pancreatitis patients and in the colon of patients with inflammatory bowel disease. Both epsilondA and epsilondC levels were found to be significantly, 3 and 28 times, respectively, elevated in the inflamed pancreatic tissue. In contrast, only epsilondC was found to be increased in affected colonic mucosa of Crohn's disease (19 times) and of ulcerative colitis patients (4 times) when compared to asymptomatic tissues. In all three cancer-prone diseases, the mean epsilondC-levels in tissues were five- to ninefold higher than those of epsilondA. Differential or impaired DNA repair pathways of these adducts, known to occur by two different glycosylases are implicated. K-ras in pancreatic tumors and K-ras and p53 in colon mucosa in long-standing inflammatory bowel disease are known to be highly mutated. The conclusion is that promutagenic etheno-DNA adducts are generated as a consequence of chronic inflammation, acting as a driving force to malignancy in cancer-prone inflammatory diseases.     

Serum-induced chronic pancreatitis

Summary Clinical research into patients with idiopathic chronic pancreatitis points to a possible immunopathogenetic process in a number of cases.In order to examine the behaviour between the exocrine pancreas under the influence of anti-rat-pancreas immune serum produced in rabbits, a 1.00 ml immune serum is administered once a week over a maximum 26 week period into Wistar-rats by intraperitoneal injection. By electrone-microscopy a much reduced production of enzymes apparently takes place, though to differing extent. There is also destruction of the basal membrane of acinocytes; the production of interstitial oedema, the new formation of collagen fibres and the proliferation of connective tissue cells. Under a conventional light microscope the first changes become noticeable after 8-12 weeks of study. These take the form of localised cell decay, deterioration and lysis of acinocytes; and an increasing non-specific inflammation. There is also the new formation of connective tissue. After 20–26 weeks the exocrine pancreas is characterised by reduction of parenchyma, acino-ductal metaplasia, chronic inflammatory infiltrates of differing density, fibrous and irregular calibres of the smaller and larger ducts.The findings are almost identical to the structural changes of chronic idiopathic pancreatitis in human beings. The results support the view of an immuno-pathologic aetiology for human chronic idiopathic pancreatitis.Supported by Deutsche Forschungsgemeinschaft     

Epithelial dysplasias in chronic pancreatitis

Summary The present 280 specimens of chronic pancreatitis were examined to determine the type and frequency of epithelial dysplasia of the duct system. The epithelial dysplasias were divided into 3 degrees of severity according to cytological and histological criteria. Dysplasia was demonstrable in 40.1% of the 280 specimens. Of these 32.9% were classified as dysplasia grade I and 7.1% as dysplasia grade II. Dysplasia grade III did not occur.The epithelial proliferations were correlated with the topography, the stage of the scarring and the degree of obstruction of pancreatic secretion. An increase in dysplasia was evident in relation to the stage of the scarring and to the obstruction of secretory outflow. In correlation with the topography of the chronic pancreatitis there was the highest frequency of epithelial dysplasias in uniformly scarred glands (47.7%). Papillary and pseudopapillary hyperplasias with atypia were demonstrated in 17.9 vs. 4.5% of the cases with epithelial proliferations.Supported by The Wilhelm-Sander Foundation, Neustadt/Donau     

Pancreolauryl test in chronic pancreatitis

Summary The pancreolauryl test was performed in 30 subjects with chronic pancreatitis, in order to evaluate its behavior in relation to the duration of the clinical history and the presence of pancreatic calcifications, diabetes mellitus, jaundice, and pancreatic pseudocysts.A significant inverse linear correlation was found between the onset of symptoms and FDL test values. While calcifications and diabetes were present in patients with both normal and abnormal test results, those with pseudocysts or jaundice always had pathological results.Abbreviations FDL Test Fluorescein-dilaurate test Supported in part by Centro Regionale di Alta Specializzazione per lo Studio delle Malattie del Fegato e del Pancreas. Conducted under the auspices of the R. Farini Association for Gastroenterological Research     

HLA antigens in chronic pancreatitis

Since immunological and hereditary factors may be important in chronic pancreatitis, histocompatibility antigens of classes I and II were studied in 50 British Caucasian patients, after exclusion of insulin-dependent diabetics for whom HLA associations are recognised. Chronic pancreatitis was defined by at least two independent criteria, and only subjects with alcohol-related and idiopathic disease were included. In 22 patients (21 male), weekly ethanol intake had chronically exceeded 100 g (usually substantially so); the remaining 28 had idiopathic chronic pancreatitis (ICP). Twenty patients (40%) had autoantibodies, in 11 (22%) to gastric parietal cells. Nine of those with ICP (three male) had parietal cell antibody, more than expected for the age/sex distribution. There were overall increased frequencies of HLA Cw5 and B44. In ICP there were increased frequencies of HLA A25 and Cw1, and a decreased frequency of B7. In patients with alcohol-related disease there were increased frequencies of Cw5 (50.0% vs control 15.9%), B44 (54.5% vs 29.4%), and DR4 (61.1% vs 33.6%). The increased frequency of Cw5 in alcohol-related disease alone remained significant after correction (p less than 0.05). A hypothesis that hereditary and possibly immunological factors may contribute to the aetiology of chronic pancreatitis is supported.     

Sialadenitis in a patient with ulcerative colitis and autoimmune pancreatitis type 2

Autoimmune pancreatitis (AIP) is a distinct form of chronic pancreatitis that has been increasingly recognised over the last decades and shows a good response to corticosteroid treatment. Two different forms of AIP have been characterized. Type 1 AIP is the pancreatic manifestation of IgG4-related disease and often affects multiple organ systems. In contrast, type 2 AIP is confined to the pancreas and involvement of extra-pancreatic organs has previously only very rarely been reported, except for an association with inflammatory bowel disease. The hallmark lesion of type 2 AIP is the granulocyte epithelial lesion (GEL), showing infiltration of neutrophilic granulocytes in the epithelium of pancreatic ducts and their accumulation in the duct lumen. We present a 61-year-old female patient who underwent pancreaticoduodenectomy with a postoperative histological diagnosis of type 2 AIP. Three months later, she underwent colectomy and was diagnosed with ulcerative colitis. One year later, she presented with swelling and pain of the right-sided submandibular salivary gland which was resected. Sialadenitis with lymphoplasmacytic inflammation, obliterative phlebitis, fibrosis and frequent accumulation of neutrophilic granulocytes in ducts, reminiscent of GELs, without IgG4-positivity or epitheloid cell granulomas, was found. Later, she presented with swelling and pain related to the left-sided submandibular gland, which resolved after steroid treatment. We describe the clinical, histological and immunohistochemical findings in this patient. It may be hypothesized that the sialadenitis may represent a rare extrapancreatic manifestation of, alternatively a rare association with, type 2 AIP or ulcerative colitis.     

Exocrine and endocrine pancreatic disorders in chronic pancreatitis

A many-year prospective follow-up of patients with chronic pancreatitis has shown that the development of carbohydrate metabolism disorders in such patients is always preceded by exo-secretory pancreatic insufficiency of varying severity. Considerable enzyme-secretory pancreatic insufficiency is much more often in patients with secondary diabetes than in those with chronic pancreatitis without diabetes. Insulinemia and blood C-peptide level are regularly reduced in chronic pancreatitis with secondary diabetes but are normal in the patients with less manifest disturbances of carbohydrate metabolism, detectable by the double glucose tolerance test. Blood glucagon is increased in both groups of patients, but more so in those with secondary diabetes. A high direct correlation of the beta-cell activity and the pancreatic enzymes debit are characteristic of patients suffering from chronic pancreatitis with secondary diabetes, as well as a negative correlation, equally high, between the blood glucagon level and the pancreatic enzymes debit in the duodenal contents.     

The endocrine pancreas in chronic pancreatitis

Summary The endocrine pancreatic tissue from patients with severe primary chronic pancreatitis (n=6), secondary chronic pancreatitis due to duct obstruction by carcinoma (n=6) and non-diabetic, non-pancreatitic controls (n=4) was studied qualitatively and quantitatively using specific immunocytochemistry and electron microscopy. Grouping of variously sized islets in the sclerotic tissue (sclerosis islets), islet neoformation by ductuloinsular proliferation, and intrainsular fibrosis were the main qualitative findings. Immunocytochemical quantitation of the distribution of insulin (B), glucagon (A), somatostatin (D) and pancreatic polypeptide (PP) producing cells revealed a significant relative increase in the number of A cells and a decrease in the number of B cells of the sclerosis islets in primary chronic pancreatitis (B-44.1±9.3%:A-38.3±2.4%:D-8.6±5.1%:PP-4.6±4.1%) as well as in secondary chronic pancreatitis (B-38.0±14.3%:A-38.4±19.0%:D-9.1±5.8%:PP-14.5±23.4%) compared with controls (B-71.1±8.1%:A-24.3±5.5%:D-8.0±2.8%:PP-0.5±0.4%). The number of PP cells was significantly increased in primary chronic pancreatitis only. It is suggested that scarring of the exocrine pancreas affects islet composition, probably by impairment of the local circulation and of glucose diffusion, thus leading to reduction of the number and glucose sensitivity of B cells. The hyperplasia of A and PP cells appears to be a secondary phenomenon due to the loss of B cells.     

Galectin-1 and galectin-3 in chronic pancreatitis

Galectin-1 and galectin-3 have important functions in cell-cell interactions, cell adhesion to extracellular matrix, the organization of extracellular matrix, and tissue remodeling. To assess their potential role in chronic pancreatitis (CP), we examined their expression by Northern blot analysis, in situ hybridization, immunohistochemistry, and Western blot analysis in normal and CP pancreatic tissues. Northern blot analysis revealed a 4.5-fold increase of galectin-1 mRNA (p < 0.01) and a 3.8-fold increase of galectin-3 mRNA (p < 0.01) in CP samples compared with normal controls. In situ hybridization analysis of normal pancreas indicated low abundance of galectin-1 mRNA in fibroblasts, whereas galectin-3 mRNA was moderately present in ductal cells. CP samples exhibited moderate to intense galectin-1 mRNA signals in fibroblasts, whereas galectin-3 mRNA signals were intense in the cells of ductular complexes and weak in the degenerating acinar cells. In addition, intense galectin-1 and galectin-3 mRNA signals were present in nerves of normal and CP samples. Immunohistochemistry showed a distribution pattern of galectin-1 and galectin-3 similar to that described for in situ hybridization. Relative quantification of galectin-1 and galectin-3 protein by immunoblotting revealed an increase of 3.2-fold and 3.0-fold, respectively, in CP compared with normal controls. There was a significant correlation between galectin-1 and fibrosis and between galectin-3 and fibrosis and the density of ductular complexes. Up-regulation of galectin-1 in fibroblasts and galectin-3 in ductular complexes suggests a role of these lectins in tissue remodeling in CP. Galectin-1 might participate in ECM changes, whereas galectin-3 seems to be involved in both ECM changes and ductular complex formation.     

Sucrase-isomaltase expression in chronic ulcerative colitis and dysplasia.

Sucrase-isomaltase (SI) is a mucosal disaccharidase that is present in normal small intestine and fetal colon. It also has been noted in colonic adenomas and adenocarcinomas. We used a polyclonal antibody to human SI to investigate enzyme presence and utility in detecting dysplastic changes in chronic ulcerative colitis. Sections from 32 cases were reviewed for the presence or absence of active colitis and dysplasia. Immunostaining of these cases for SI was performed and the results were reported based on location of immunoreactivity (ie, membrane and cytoplasmic staining in superficial and crypt epithelial cells) and percentage of positivity. Of 81 sections examined, 48 were rated negative for dysplasia (23 inactive colitis, 20 active, and five probably negative) and 28 were rated positive (eight low grade and 20 high grade). Surface membrane staining of epithelial cells was noted in all 28 dysplastic slides and positive cases (sensitivity, 100%) but also in 29 of 48 negative sections (P less than .001). In contrast, cytoplasmic positivity was present in 25 of 28 dysplastic and in only two of 48 negative slides (P less than .0001). The presence of cytoplasmic staining of SI in the superficial or crypt cells revealed a sensitivity of 92% and a specificity of 94%. There were five additional sections rated as indefinite for dysplasia (probably positive or unknown); two showed staining patterns typical of negative slides and three showed positive staining patterns. Of the 18 samples of transitional mucosa next to areas of dysplasia, surface membrane staining of SI was seen in all samples and cytoplasmic staining was seen in 15. We conclude that membrane staining of SI can be detected in inflammatory, regenerative, and dysplastic mucosa in ulcerative colitis. Cytoplasmic staining, however, correlates strongly with the presence of dysplastic change and may help in its detection.