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Background: Little is known about the etiopathogenesis of chronic pancreatitis, due mainly to the lack of simple animal models suitable to study inflammatory and fibrogenetic processes in the pancreas., Aims: The purpose of this study was to examine whether transient congestion of pancreatic fluid flow alone or slight ductal injury alone is sufficient, or where both are required, to induce chronic pancreatic injury., Methods: Three different models of pancreatitis were tested in rats induced by retrograde intraductal infusion of 40 μl/100 g body weight of 0.01% agarose (group A), 40 μl/100 g body weight of 0.1% sodium taurocholate (group T), or a mixture of the two solutions (group M). Histological alterations of the pancreas were examined by hematoxylin-eosin staining, changes in type IV collagen structure were studied by immunostaining, and the gelatinolytic activity of latent and active matrix metalloproteinase-2 (MMP-2) was analyzed by zymography., Results: In group A and T rats, histological alterations of the pancreas and the gelatinolytic activity of MMP-2 returned to baseline levels by day 14, and immunoreactivity for type IV collagen appeared as continuous lines along the basement membrane. In group M rats, however, acinar damage, fibrosis and fatty degeneration were observed even on day 56, and type IV collagen was detected as discontinuous lines until day 56. MMP-2 was significantly elevated from day 5 to day 42., Conclusions: Co-existence of transient stasis of pancreatic fluid flow, together with mild damage to the pancreatic duct and acinar cells, exert synergistic effects on the development of persistent pancreatic injury with continuous disorganization of type IV collagen in the basement membrane of the ducts.

As appropriate therapies for pancreatic fibrosis and inflammation are limited, prognosis of chronic pancreatitis has not improved to date. Recent studies have shown that statins improve inflammation and fibrosis in several organs. We therefore examined the therapeutic effect of pravastatin on progression of chronic pancreatitis by starting this treatment after induction of pancreatic fibrosis in rats. Chronic pancreatitis was induced by continuous pancreatic ductal hypertension (PDH) for 14 days according to our previous study. Pravastatin at a dose of 10 mg/kg/day was administrated directly into the duodenum via cannula from 2 days after induction of PDH. Progression of pancreatic fibrosis and expression levels of transforming growth factor-β1 and tumor necrosis factor-α mRNA were markedly attenuated after commencement of pravastatin compared with untreated group with PDH. In addition, pravastatin treatment markedly improved pancreatic exocrine function and significantly elevated expression level of interleukin (IL)-10 and superoxide dismutase activity in the pancreas compared with the untreated group with PDH. These results revealed that pravastatin substantially attenuates the progression of pancreatic inflammation, fibrosis and exocrine dysfunction probably by its anti-oxidative property and overproduction of IL-10 in animal model of chronic pancreatitis. These results provide an experimental evidence that pravastatin exerts beneficial effect for progression of chronic pancreatitis.

In Japan, we are now using the clinical diagnostic criteria for chronic pancreatitis (CP) that were revised in 2001 to add the findings of magnetic resonance cholangiopancreatography to the criteria compiled by the Japan Pancreas Society (JPS) in 1995. Because the current criteria are set for diagnosing advanced CP, they are unlikely to improve patients' prognoses. In addition, they seem unsuitable for current clinical practice because exocrine pancreatic function tests, which have become obsolete in Japan, are included in the diagnostic factors. For these reasons, the Research Committee on Intractable Pancreatic Diseases supported by the Ministry of Health, Labour and Welfare of Japan, the JPS and the Japanese Society of Gastroenterology have revised the criteria. The revised criteria are unique in that they contain an introduction to the concept of early CP. It is a challenge aimed at improvement of the long-term prognosis of CP patients by early diagnosis and therapeutic intervention in this disease. We need to determine and clarify the clinico-pathological outcome of early CP by a prospective long-term follow-up of the patients in this category.

Objectives: We examined the effect of the overexpression of Smad6 on pancreatic fibrosis after chronic pancreatic injury., Methods: Chronic pancreatic injury was induced in transgenic mice overexpressing Smad6 (Tg mice) in acini and wild-type (Wt) mice by 3 episodes of acute pancreatitis per week for 1 to 4 consecutive weeks. Acute pancreatitis was elicited by 6 intraperitoneal injections of caerulein (Cn) at 50 microg/kg of body weight at hourly intervals. Pancreatic fibrosis was evaluated by histological examination and hydroxyproline content before and 1, 2, 3, and 4 weeks of repetitive episodes of Cn-induced acute pancreatitis. We further determined transforming growth factor beta1 (TGF-beta1) messenger RNA expression and trypsin activity in the pancreas., Results: After repetitive episodes of acute pancreatitis, pancreatic fibrosis in Tg mice was significantly severer than that in Wt mice at all time points (weeks 1-4). The expression of TGF-beta1 messenger RNA and the activity of trypsin in the pancreas in the Tg mice were significantly high compared with those in the Wt mice at all corresponding time points after repetitive episodes of acute pancreatitis., Conclusions: These results demonstrated that overexpression of Smad6 in acini enhanced the development of pancreatic fibrosis after chronic pancreatic injury.

Background: Autoimmune pancreatitis (AIP) is a rare type of chronic pancreatitis caused by an autoimmune abnormality. It is well known that high serum concentrations of IgG4 are helpful for making a diagnosis of AIP; however, it is unclear whether there are abnormalities in the production of other immunoglobulins in AIP., Methods: We examined the immune condition of AIP patients before and after glucocorticoid treatment, focusing on serum levels of IgG, IgG4, IgM and IgA, and compared the results with those in other hepato-pancreatic diseases, such as autoimmune hepatitis, primary biliary cirrhosis, chronic pancreatitis and pancreatic carcinoma., Results: IgM and IgA were decreased in patients with untreated AIP. IgM and IgG or IgG4 were negatively correlated in patients with AIP. The ratios of IgG to IgM and IgG to IgA in patients with AIP were significantly increased compared with the other diseases. The diagnostic sensitivity of IgG to IgM and IgG to IgA was 0.800 and 0.950, and the specificity of each ratio was 0.703 and 0.728, respectively, in the differentiation of AIP from the other diseases. IgM was not significantly changed after glucocorticoid treatment in the patients with AIP, while IgG, IgG4 and IgA decreased., Conclusions: The ratios of IgG to IgM and IgG to IgA may serve as novel diagnostic markers to differentiate AIP from other hepato-pancreatic diseases. Furthermore, low concentrations of IgM and IgA may be involved in the pathogenesis of AIP.

Background: Because autoimmune pancreatitis is a new disease entity, there are no data with regard to its prevalence., Methods: To estimate the number of patients with autoimmune pancreatitis in Japan, we randomly selected hospitals using stratification and asked them how many patients they had with pancreatitis in 2002 who fulfilled the diagnostic criteria for autoimmune pancreatitis as proposed by the Japan Pancreas Society., Results: The number of patients with autoimmune pancreatitis who visited hospitals in Japan in 2002 was approximately 900 (95% confidence interval; range 670-1100). The male : female ratio was 2.85 : 1, and the age of disease onset in 95% of the patients was over 45 years., Conclusions: The prevalence of patients with autoimmune pancreatitis in Japan was estimated to be 0.82 per 100,000. Autoimmune pancreatitis was predominantly seen in men past middle age (over the age of 45 years).

Autoimmune pancreatitis (AIP) is a unique form of chronic pancreatitis generally observed in aged people and characterized by the presence of autoantibodies,(1-3) elevated levels of immunoglobulins,(4) enlargement of the pancreas (diffuse or focal) on ultrasonography (US) or computed tomography (CT),(1-3,5) diffuse narrowing of the main pancreatic duct (MPD) with an irregular wall,(1,3,5-8) and pathologic features of dense lymphoplasmacytic inflammation and fibrosis, as well as a favorable response to steroid therapy.(1-3,5,8) The clinical findings in AIP include obstructive jaundice secondary to biliary stenosis, mild epigastralgia, and diabetes mellitus. The clinical, laboratory, and radiological features respond promptly to oral steroid therapy.(1-3,5,6,8) Although prompt response to oral steroid therapy may be helpful in the differential diagnosis of AIP, careful imaging studies are necessary to exclude cancer of the pancreas or common bile duct (CBD).

Autoimmune pancreatitis (AIP) has been characterized by unique clinical imaging, immunological findings, and the effectiveness of steroid therapy. A set of clinicopathological criteria for AIP was proposed by the Japan Pancreatic Society in 2002, and AIP has come to be widely recognized among general digestive clinicians. However, the indication of steroid therapy for AIP is still not well established, and furthermore the therapeutic doses and method of administration of steroid therapy is also unclear. Recently, an epidemiological survey of all the treatments used for AIP in Japan was conducted by the Research Committee of Intractable Pancreatic Diseases, and their report "Consensus for a Treatment of Autoimmune Pancreatitis" was produced. In a comparison of the results of steroid therapy and nonsteroid therapy for AIP in relation to the rate of complete remission, the recurrence rate, and the period needed to guarantee complete remission, it was thought that the administration of a steroid should be a standard therapy for AIP. However, if the diagnosis of AIP is still uncertain, steroid therapy should be given with caution. In addition, even when AIP still appears to be possible after a course of steroid therapy, a re-evaluation should be carried out taking pancreatic carcinoma into consideration. An initial steroid dose of 30-40 mg per day is recommended. With continuous and careful observations of the clinical manifestations, laboratory data, and imaging findings after administration of the initial dose of steroid for 2-4 weeks, the quantity of steroid can be reduced gradually to a maintenance dose in 2-3 months, and then reduced to 2.5-5 mg per day after remission. The recommended period of maintenance treatment is still unclear, but the administration of the steroid could be stopped after a period of about 6-12 months of treatment, although the patient should be monitored for clinical manifestations of improvement. In addition, the patient's progress should be followed taking recurrence into consideration. In order to evaluate the effectiveness of steroid therapy, follow-up observations should include biochemical examinations of blood findings such as serum gamma-globulin, IgG, and IgG 4, imaging findings, and clinical manifestations such as jaundice and abdominal discomfort.

Background: We aimed to determine the cumulative rate of diabetes mellitus (DM) and the risk factors for DM in patients with chronic pancreatitis (CP) in Japan., Methods: We conducted a follow-up survey of CP in 2002 in patients registered as having CP in 1994, and confirmed 656 patients to be checked in regard to the survey items concerning diabetes. We analyzed the cumulative rate of DM and the risk factors for DM over an 8-year follow up period., Results: In 1994, 35.1% of 656 CP patients had DM, and the incidence of diabetes had increased to 50.4% in 2002. Of 418 patients without diabetes in 1994, 28.9% (121/418) were newly diagnosed with DM in 2002. Alcoholic CP was the most common type of CP in patients with newly developed diabetes, accounting for 67.8%. The incidence of DM was highest in those with alcoholic CP (34.3%) followed by idiopathic CP (23.0%). The risk of diabetes increased 1.32-fold after the onset of pancreatic calcification. Of 121 patients with newly diagnosed DM in 2002, 37 (30.6%) had pancreatic stones in 1994 and 49 (40.5%) had a stone in 2002. The highest incidence of newly diagnosed DM was observed in patients with continuous alcoholic intake (40.9%). Patients treated with camostat mesilate developed DM less frequently than those without camostat mesilate., Conclusions: The present study showed that the incidence of DM in patients with CP increased with time. Of 418 CP patients without DM in 1994, 28.9% developed DM over a period of 8 years. Continuous alcoholic intake aggravated CP and increased the risk of DM in those with CP.

In Japan, the number of patients with both chronic pancreatitis (CP) and pancreatic cancer (PC) is increasing. A nationwide survey on CP revealed that the total number of patients treated for CP in Japan in 2002 was estimated as 45,200 (95% confidence interval, 35,600-54,700), and 20,137 patients died of PC in 2002. Alcoholic pancreatitis was the most common type of pancreatitis (67.5 %). Cigarette smoking was an independent and significant risk factor for CP. The risks of pancreatic and nonpancreatic cancers increased in the course of CP. While alcohol consumption may increase the risk of PC via CP, smoking was important as a risk factor for both CP and PC. The increasing incidence of PC was closely related to the increasing intake of animal fat. Lifestyle in patients with CP appeared to be the same as that in patients with PC. Environmental factors such as lifestyle in combination with genetic factors may increase the risk for both CP and PC. Therefore, changing and improving lifestyle habits such as drinking, smoking and nutrition may reduce the risks for both CP and PC.

Objectives: Recent studies have demonstrated that synthetic protease inhibitors could ameliorate the progression of pancreatic fibrosis in some animal models. Since oral administration of protease inhibitors increases the plasma cholecystokinin (CCK) levels and causes hypertrophy of the pancreas in rats, there is a possibility that the protease inhibitor inhibits fibrosis in the pancreas via endogenous CCK release. We examined the effects of camostat, a synthetic protease inhibitor, on histopathologic changes in Otsuka Long-Evans Tokushima Fatty (OLETF) rat that has genetically no expression of CCK-1 receptor and displays inflammation and degeneration of the pancreas., Methods: Three groups of OLETF rats received a camostat-rich diet (200 mg/100 g normal diet) from 12 to 28 weeks of age or from 12 or 28 weeks of age to the age of 72 weeks, while the fourth group received standard rat diet., Results: Pancreatic wet weight and pancreatic contents of protein, DNA, amylase, lipase, and trypsin in camostat-treated rats were significantly higher than those in the untreated control rats. Immunohistochemical studies of the pancreas showed that expressions of interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, and alpha-smooth muscle actin in camostat-treated rats were greatly suppressed compared with those in the untreated control rats. Atrophy and fibrosis in the pancreas observed in the untreated control rats were not found in camostat-fed rats., Conclusion: The results of the present study suggest that camostat greatly inhibits pancreatic inflammation and prevents and reverses fibrosis and atrophy of the pancreas in the genetically obese and CCK-1 receptor-deficient OLETF rats.