Chymotrypsin C mutations in chronic pancreatitis

Chronic pancreatitis is a persistent inflammatory disorder characterized by destruction of the pancreatic parenchyma, maldigestion, and chronic pain. Mutations in the chymotrypsin C (CTRC) gene encoding the digestive enzyme CTRC have been shown to increase the risk of chronic pancreatitis in European and Asian populations. Here, we review the biochemical properties and physiological functions of human CTRC, summarize the functional defects associated with CTRC mutations, and discuss mechanistic models that might explain the increased disease risk in carriers.     

Diagnosis of Chronic Pancreatitis by Endoscopic Ultrasonography

Abstract: This study evaluates the usefulness of endoscopic ultrasonography in the diagnosis of chronic pancreatitis. 52 patients with chronic pancreatitis, which included 15 cases of mild pancreatitis, 19 cases of moderate pancreatitis and 18 cases of advanced pancreatitis, were diagnosed by endoscopic retrograde cholangiopancreatography and further investigated by endoscopic ultrasonography. The 4 main findings of 1) dilatation of the main pancreatic duct, 2) irregularity of the main pancreatic duct, 3) inhomogeneity of the pancreatic parenchyma and, 4) irregular configuration of the pancreas were reviewed. In all of the 18 cases of advanced pancreatitis, irregularity of the main pancreatic duct, inhomogeneity of the pancreatic parenchyma and irregular configuration of the pancreas were seen. 89% of these patients had dilatation of the main pancreatic duct. In the patients with moderate pancreatitis, on the other hand, all 4 findings occurred with a frequency of between 58% to 95%. In the patients with mild pancreatitis, irregularity of the main pancreatic duct, inhomogeneity of the pancreatic parenchyma and irregular configuration of the pancreas occurred at a rate of 40% to 93%, and dilatation of the main pancreatic duct occurred rarely in only 13% of the patients. We were able to detect abnormalties in the pancreatic parenchyma by endoscopic ultrasonography even in the early stages of chronic pancreatitis, and this suggests that this technique may be useful in the diagnosis of mild pancreatitis, which usually causes quite minor abnormal changes in the main pancreatic duct.     

Chronic Alcoholic Pancreatitis with Pancreas Divisum

The mechanism for the onset of chronic alcoholic pancre-atitis(CAP) involves many unresolved questions. We (1,2) have succeeded in creating an animal model of CAPby inducing mild stenosis of the pancreatic duct in experi-mentalanimals given alcohol. The CAP seen in this modelis akin to that seen in humans. This means that pancreaticduct-related factors play an important role in the onset ofCAP.     

Autoantibodies in Chronic Pancreatitis

In 60 consecutive patients clinically suspected of having chronic pancreatitis the serum concentration of the immunoglobulins (IgA, IgG, IgM), the IgG- and IgA-type non-organ-specific autoantibodies against nuclear material (ANA), smooth and striated muscle, mitochondria, basal membrane, and reticulin, and the IgG- and IgA-type pancreas-specific antibodies against islet cells, acinus cells, and ductal cells (DA) were estimated blindly. In 23 of the patients chronic pancreatitis was verified, whereas chronic pancreatitis was rejected in 37 patients (control group). IgG and IgA were found in significantly higher concentrations in the patients with chronic pancreatitis than in the control group but within the normal range. ANA and DA occurred very frequently in both groups but with no statistical difference. Other autoantibodies only occurred sporadically. The findings of this study do not support the view of an immunological pathogenesis in chronic pancreatitis.     

Analysis of Pancreatic Elastase-1 Concentrations in Duodenal Aspirates from Healthy Subjects and Patients with Chronic Pancreatitis

Fecal pancreatic elastase 1 (PE-1) has been advocated as a noninvasive marker of pancreatic function and allows detection of moderate and severe exocrine insufficiency. Few studies have evaluated the utility of measuring PE-1 in duodenal fluid for the diagnosis of pancreatic insufficiency. Our purpose was (1) to determine the feasibility of measuring PE-1 concentrations in duodenal aspirates obtained through our endoscopic pancreatic function test (ePFT) in healthy subjects and patients with chronic pancreatitis (CP) and (2) to determine correlations between duodenal PE-1 concentrations and bicarbonate and lipase concentrations in duodenal fluid. Healthy subjects (HS) and CP patients underwent an ePFT with CCK or secretin. CP was defined as endoscopic retrograde pancreatography (ERP) Cambridge class III-IV, endoscopic ultrasound (EUS) score >5, or presence of pancreatic calcifications on CT scan. Duodenal fluid PE-1, lipase, and bicarbonate concentrations were measured in each study group. Duodenal lipase and bicarbonate concentrations were measured using an autoanalyzer (Roche Diagnostics, Indianapolis, IN). PE-1 was measured using an ELISA (Genova Diagnostics, Asheville, NC). Ten HS and 10 CP patients were studied. In the CCK test the median peak lipase for HS and CP was 1605 and 113 IU/L, respectively (P < 0.008). In the secretin test the median peak bicarbonate for HS and CP was 102 and 40 mEq/L, respectively (p < 0.008). Median PE-1 concentrations for HS and CP were 317 and 63 microg/ml, respectively, after CCK stimulation (p = 0.046) and 87 and 17 microg/ml, respectively, after secretin stimulation (p = 0.033). Statistically significant correlations were found between [PE-1] and peak [lipase] (r = 0.83, P < 0.001), as well as [PE-1] and peak [HCO3(3)-] (r = 0.65, P = 0.037). Conclusions are as follows: (1) PE-1 concentrations can be measured from duodenal fluid obtained by endoscopic aspiration. (2) Duodenal fluid PE-1 concentrations are decreased in CP compared to HS. (3) Duodenal fluid [PE-1] has an excellent correlation with [lipase] and therefore is a marker of acinar cell function. (4) Secretin-stimulated endoscopic function testing with measurement of bicarbonate and PE-1 may provide a simultaneous assessment of both ductal cell and acinar cell function.     

Pancreatic Sphincterotomy and Pure Pancreatic Juice Collection for Treatment of Chronic Pancreatitis

Abstract: After our introduction of endoscopic pancreatic sphincterotomy for treatment of chronic pancreatitis in 1985, our interest has been focused to the value of pure pancreatic juice collection with or without pancreatic sphincterotomy for management of chronic pancreatitis. Through pancreatic sphincterotomy, pain relief was obtained in 13 out of 16 cases with moderate and marked chronic pancreatitis. After pancreatic sphincterotomy extraction of pancreatic calculi using basket forceps was done successfully in 2 of these cases, Spontaneous stone passage occured in the other 2. In pure pancreatic juice collection without pancreatic sphincterotomy, pain relief was seen in 6 out of 13 cases with mild and moderate chronic pancreatitis. The protein plug was simultaneously aspirated during the procedure in 3 cases. Recently, we have indicated in these patients both pancreatic sphincterotomy and pure pancreatic juice collection and noted pain relief was obtained in all of the 8 cases with this approach. With an improvement in the technology of pancreatic drainage, these endoscopic treatment modalities may be possibly useful to stop the progression of chronic pancreatitis.     

慢性胰腺炎的并发症

目的：探讨慢性胰腺炎（Chronic pancreatitis,CP）并发症的发生率、临床表现及诊断,旨在提高对于CP并发症的认识。方法：回顾性分析北京协和医院1982年－2001年确诊CP的236例住院患者。所有病例均符合1983年日本胰腺病协会关于CP的诊断标准,其中经病理证实者82例。结果：236例CP患者中156例出现并发症,占66．1％。其中,胆道梗阻、狭窄41例,占236例CP的17．4％;胰腺假性囊肿40例,占16．9％,脾静脉狭窄32例,占13．6％;胰源性浆膜腔积液19例,占8．1％; 上消化道不全梗阻17例,占7．2％;消化性溃疡14例,占5．9％;邻近血管病变13例,占5．5％;合并症还涉及胰腺癌（占4．2％）、结核及胰外肿瘤。结论：CP并发症相当常见,临床表现丰富多彩,有些患者以 并发症首诊,应提高对CP并发症的认识。     

Micronutrient Antioxidant Status in Tropical Compared with Temperate-Zone Chronic Pancreatitis

Micronutrient antioxidants interact with glutathione in tissues to facilitate the disposal of reactive oxygen species and xenobiotic metabolites derived via cytochromes P450. Published evidence linking cytochrome P450I induction with chronic pancreatitis therefore led us to compare antioxidant status in patients at Manchester in the northwest of England and at Madras in the southeast of India. Serum studies in healthy volunteers showed that the biologic availabilities of selenium and α-tocopherol were equally high in the two zones but that the availabilities of β-carotene and ascorbic acid were lower in the tropical area (p< 0.001), where the ratio of ascorbic acid to total vitamin C concentration in serum was substantially reduced (p< 0.001). The serum antioxidant profiles of the chronic pancreatitis groups reflected these indigenous differences: a decrement in selenium and α-tocopherol was evident in both zones, whereas β-carotene and ascorbic acid values were subnormal only in the Manchester group. The concentration of inorganic sulphate in urine–an index of long-term intake of sulphur amino acids for synthesis of glutathione and other detoxifiers–was similar in controls and patients from Manchester, but levels were lower than in their Madras counterparts (p < 0.02, p < 0.01, respectively). The results suggest that culinary practices that erode the biologic availabilities of ascorbic acid and β-carotene may predispose to pancreatic oxidative stress and thereby to the changes leading to chronic pancreatitis at an early age in south India. These findings have implications for treatment and prophylaxis     

Trimetazidine has Promising Preventive Effects on Experimental Chronic Pancreatitis Rat Model

Background: It was aimed to evaluate the preventive efficacy of trimetazidine in an experimental chronic pancreatitis rat model.Methods: Chronic pancreatitis model was accomplished with caerulein and alcohol administration. In the study, 40 female Sprague Dawley rats were randomized into 5 groups containing 8 animals in each. Group 1 (chronic pancreatitis); group 2 (chronic pancreatitis + low-dose trimetazidine group); group 3 (chronic pancreatitis + high-dose trimetazidine group); group 4 (placebo group (chronic pancreatitis + saline)); group 5 (sham group). 24 hours after the last injection, all animals were sacrificed. Tumor necrosis factor-alpha, transforming growth factor-β, malondialdehyde, and glutathione peroxidase levels were tested in blood samples. Histopathologic examinations were conducted by a senior pathologist who was unaware of the group allocations.Results: Results of biochemical parameters of the trimetazidine groups (groups 2 and 3) were significantly favorable compared with the chronic pancreatitis group (group 1) (P < .05). The difference between the low-dose- and the high-dose trimetazidine group (group 3) was significant in terms of blood tests (P < .05). The difference between the low-dose trimetazidine group and the chronic pancreatitis group was not significant in terms of histopathologic scores (P > .05); however, the difference was significant between the high-dose trimetazidine group and the chronic pancreatitis group (P < .05).Conclusions: To the best of our knowledge, this current research is the first study that evaluates trimetazidine’s efficacy in the chronic pancreatitis rat model. Trimetazidine has affirmative preventive properties in the chronic pancreatitis course.     

Pancreatic Polypeptide Secretion in Patients with Chronic Pancreatitis and After Pancreatic Surgery

Aim. We investigated polypeptide (PP) secretion under basal conditions, in response to bombesin infusion and to meal ingestion in patients with chronic pancreatitis (CP) and patients after different types of pancreatic surgery. Methods. Included were patients with CP without (n=20) and with (n=30) exocrine pancreatic insufficiency, patients after duodenum preserving resection of the head of the pancreas (DPRHP; n=20), after Whipple’s procedure (n=19), following distal pancreatectomy (DP; n=12), and healthy controls (n=36). Results. In CP patients basal and bombesin stimulated PP levels were significantly (p<0.01) reduced compared to controls only when exocrine insufficiency was present. Meal-stimulated PP secretion was significantly (p<0.01−0.05) reduced in CP patients both with and without exocrine insufficiency. Plasma PP peak increments after bombesin and meal ingestion correlated significantly with exocrine function. Basal PP, meal, and bombesin-stimulated PP secretion had low sensitivities of 22%, 42%, and 60% respectively, in detecting chronic pancreatitis. In patients after pancreatic surgery that included pancreatic head resection (DPRHP or Whipple operation) basal and stimulated PP secretion were significantly (p<0.01−0.05) reduced. Conclusion. Basal and meal or bombesin-stimulated PP levels are significantly reduced in patients with CP only when exocrine insufficiency is present. Determination of plasma PP levels has low sensitivity and is not useful in detecting chronic pancreatitis without exocrine insufficiency. In patients after pancreatic surgery, PP secretion is dependent on the type of operation (head vs tail resection).     

A Case of Chronic Pancreatitis Associated with a Pancreato-gastric Fistula

Abstract: A 51-year-old man presented complaining of frequent diarrhea. An ultrasonography and abdominal CT scan revealed a tumor in the tail of the pancreas. An endoscopic retrograde pancreatography revealed contrast medium flowing over the pancreas through the main pancreatic duct. A balloon cathether was then passed into the pancreatic duct, and the scope alone was retracted to the stomach. Maintaining the stomach under endoscopic observation, ICG was injected through the balloon catheter, whereupon it was seen to flow out from two small depressions in the center of a small elevated lesion in the posterior wall of the upper gastric corpus. Based on these endoscopic findings, a diagnosis of chronic pancreatitis with an associated pancreato-gastric fistula was made.     

善得定治疗急性胰腺炎的体会

作者对比观察了善得定对急性胰腺炎的治疗作用，其剂量为0.1-0.15mg，每4－6h一次，皮一注射。在85例水肿型胰腺炎中，15例应用善得定治疗。结果显示，善得定治疗组转手术率显著低于非善得定组（P＜0．05），未合并感染的12例坏死性胰腺炎均采取非手术治疗，其中3例应用善得定治疗，其合并症全部消失，明显优于对照组。合并感染的67例坏死性胰腺炎均予以手术治疗，病情严重的14例，用善得定治疗，结果显示可减少并发症及其严重度。     

Assimilation of Wheat Starch in Patients with Chronic Pancreatitis Positive Effect of Enzyme Replacement

Pancreatic insufficiency due to chronic pancreatitis may lead to symptomatic malabsorption of both starch and fat. The absorption capacity of wheat starch has not been studied previously in patients with chronic pancreatitis, although this carbohydrate is a quantitatively important component of the Western diet. We studied the absorption of wheat starch and the effect of pancreatic enzyme substitution in seven patients with chronic pancreatitis and steathorrea. The malabsorption was determined from hydrogen breath tests with lactulose standards as reference. Without enzyme substitution, wheat starch (50 g) was absorbed to a lesser extent than in healthy controls (p < 0.05). The mouth-to-cecum transit time was prolonged and correlated positively to the fat excretion before substitution with pancreatic enzymes (s` = 1). The enzyme substitution increased the absorption of wheat starch to values seen in healthy controls (p < 0.05) and reduced the mouth-to-cecum transit time by 19.8%.     

Genetic Polymorphisms of GSTT1, GSTM1, GSTP1, MnSOD,and Catalase in Nonhereditary Chronic Pancreatitis: Evidence of Xenobiotic Stress and Impaired Antioxidant Capacity

Epidemiological studies have demonstrated a variety of potential environmental factors that may alter susceptibility to chronic pancreatitis (CP) through oxidative/xenobiotic stress; however, a direct causal and mechanistic role has not been established. We aimed (1) to determine the prevalence of functional genetic polymorphisms in the antioxidant enzymes, glutathione S-transferase GSTM-1, GSTP-1, and GSTT-1, manganese superoxide dismutase, and catalase in CP and (2) to reveal evidence of oxidative stress in patients with CP by measuring whole-blood glutathione redox status. In total, 122 patients with CP (75 alcohol-induced [AlCP], 33 idiopathic [ICP], and 13 hereditary) and 245 age- and sex-matched controls were recruited. The prevalence of the functional GSTT-1 genotype (GSTT-1*A) was significantly higher in CP (88.5%) compared to healthy controls (76%; χ² = 7.26, P = 0.007). Stratification to disease etiology demonstrated that the GSTT-1*A genotype was also significantly more prevalent among patients with ICP (94%; P = 0.02; 95% CI, 0.04–9.16) but not in those with AlCP. In 22 patients with stable CP, the whole-blood glutathione concentration (median [IQR]: 72 μmol/L [21–181 μmol/L]) and the glutathione redox ratio (GSH/GSSG) (median [IQR]: 9 (3–77]) were significantly reduced compared to those in 20 healthy volunteers (median [IQR]: 815 μmol/L [679–1148 μmol/L], P < 0.001, and 96 [52–347], P = 0.005, respectively). We conclude that the GSTT-1 functional genotype is associated with ICP. Evidence of altered glutathione redox status suggests that this disease modification may be a consequence of oxidative stress or the bioactivation of xenobiotics.     

Pancreatic Secretory Proteins in Sera from Rats before and after Induction of Experimental Pancreatitis

This study has traced the behavior of rat anionic trypsin-like immunoreactivity and pancreatic secretory trypsin inhibitor (PSTI) immunoreactivity in the serum of rats undergoing bile-pancreatic duct infusions of buffered solutions with and without the addition of the bile salt taurocholate. Enzymatic analysis of α-amylase was also done. A mild pancreatic inflammation followed infusion of buffer alone, as determined by gross inspection of the pancreas and the behavior of serum levels of the above proteins. Animals infused with buffer and 4% taurocholate had major inflammatory changes, including gross hemorrhage into the gland, and marked elevations in serum levels of the three proteins studied. Graphic analysis of the serum levels revealed distinct sharp rises in the serum levels of all three proteins in the taurocholate group. In the buffered saline group only an initial sharp rise was present, followed by a prolonged decrease back towards base-line values. The immunoreactive trypsin in the taurocholate group was present in three fractions with different molecular weights: trypsin in complex with protease inhibitors, trypsinogen, and degradation products. PSTI immunoreactivity showed the molecular size of free inhibitor and that of degradation products. The presence of trypsin in complex with protease inhibitors indicates the formation of active trypsin during acute pancreatitis, which is further supported by the presence of degradation products of trypsin and PSTI.     

Determination of Plasma Trypsin-Like Activity in Healthy Subjects, Patients With Mild to Moderate Alcoholic Chronic Pancreatitis, and Patients With Nonjaundice Pancreatic Cancer

Trypsin-like activity is released after stimulation of the exocrine pancreas. We investigated under basal conditions and after stimulation by a meal whether patients suffering from pancreatic disorders differ with respect to plasma trypsin-like activity (PTLA). In 45 subjects (healthy volunteers: n = 18, mild/moderate alcoholic chronic pancreatitis: n = 16, nonjaundice pancreatic cancer n = 7, and calcifying chronic pancreatitis: n = 4), basal and postprandial levels of PTLA were measured over a period of 2 hours. Basal plasma levels were similar in the first 3 groups. After stimulation, healthy volunteers and patients with pancreatic cancer showed significant decreases in trypsin-like activity; however, plasma levels did not decrease in patients with mild/moderate chronic pancreatitis (P < .001). Healthy individuals demonstrate a consistent decrease in postprandial trypsin-like plasma activity. This response is not altered in patients with pancreatic cancer, and it is not seen in patients with mild/moderate alcoholic chronic pancreatitis.     

Chronic pancreatitis in Chinese children: Etiology,clinical presentation and imaging diagnosis

Background and Aims: There is a paucity of literature regarding the clinical profile of chronic pancreatitis (CP) in children. The aims of this retrospective study were to determine the etiology and clinical presentation, and to present our experience in diagnosing CP in children in China. Methods: Clinical data of children who were treated for CP at Changhai Hospital from January 1997 to August 2006 were reviewed. Results: A total of 427 CP patients presented to our center. There were 42 (9.8%) children with CP, including 21 males and 21 females, with a mean age of 11.7 years at the first onset. The main etiological factor was idiopathic (73.8%). Of the patients, 78.5% had episodes of mild to moderate abdominal pain and 54.8% had multiple (≥ 4) episodes. The mean duration of symptoms prior to the diagnosis was 41.6 months and a definite diagnosis was not made until 2 years later in 57.1% of these patients. The positive rates of ultrasound (US), computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) (or magnetic resonance imaging [MRI]) for detecting ductal changes and intraductal stones or pancreatic calcification were 51.4% and 45.4%, 71.4% and 87.5%, 80.0% and 61.5%, respectively. Conclusion: The main etiological factor of Chinese children with CP is idiopathic. The main symptom in these patients is multiple episodes of mild to moderate abdominal pain, which often lead to a delay in the definite diagnosis. CT and MRCP (or MRI) should be used as the first investigation in the evaluation of these cases.     

糜蛋白酶C在胰腺炎和胰腺癌发生发展中的作用

糜蛋白酶C(CTRC)是由胰腺腺泡细胞合成,胰腺导管细胞分泌的蛋白酶原,属于丝氨酸糜蛋白酶家族。其主要作用是调控胰蛋白酶的活化与降解的平衡,维持胰腺组织结构和功能的完整性。CTRC基因位点突变,使得胰蛋白酶原的活化及胰蛋白酶的降解异常,导致慢性胰腺炎的发生。CTRC表达下调甚至缺失可能与胰腺癌的发生及转移有关。介绍了CTRC基因的结构、生物学功能,及其在胰腺炎、胰腺癌发生发展中的作用机制。