Trypsin secretion and turnover in patients with acute pancreatitis

Studies in humans have shown that pancreatic enzyme secretion is reduced during acute pancreatitis. It is not known, however, whether the reduction is due to impaired synthesis or disruption of the secretory pathway. The rate of secretion and turnover of trypsin was measured in 12 patients with acute pancreatitis of variable etiology and severity (median Ranson's score 2.5, range 0-5, 4 with severe necrotizing disease) and eight healthy volunteers by 4-h primed/continuous intravenous infusions of 1-(13)C-labeled l-leucine, and collection of pancreatic secretions by duodenal perfusion and sampling. Trypsin secretion was reduced from 476 +/- 73 to 153 +/- 60 U/h (means +/- SE, P = 0.005) in acute pancreatitis, with the greatest reductions being observed in patients with necrotizing disease (32 +/- 7 U/h, P = 0.003). The time for newly labeled trypsin to first appear in digestive juice was not, however, delayed in pancreatitis patients (87.2 +/- 11.1 vs. 94.7 +/- 4.9 min); on the contrary, there was an early appearance of newly labeled trypsin at 30 min in patients with severe necrotizing pancreatitis (P < 0.05). Calculated zymogen pool turnover was unchanged, but pool size was decreased (P = 0.01). Despite low rates of luminal secretion, trypsin continues to be synthesized in patients with acute pancreatitis. Our findings could be explained by post-Golgi leakage of enzymes from acinar cells or by loss of synthetic function in some cells with preservation in others.     

Apoptosis of pancreatic acinar cells in acute pancreatitis: is it good or bad?

Acute pancreatitis is a disease of variable severity in which some patients experience mild, self-limited attacks while others manifest a severe, highly morbid, and frequently lethal attack. The events that regulate the severity of acute pancreatitis are, for the most part, unknown. Several recent studies have suggested that the acinar cell response to injury may be an important determinant of disease severity. In these studies, mild acute pancreatitis was found to be associated with extensive apoptotic acinar cell death while severe acute pancreatitis was found to involve extensive acinar cell necrosis but very little acinar cell apoptosis. These observations have led to the hypothesis that apoptosis might be a favorable response to acinar cell and that interventions which favor induction of apoptotic, as opposed to necrotic, acinar cell death might reduce the severity of an attack of acute pancreatitis. This review aims to discuss our current understanding of the contribution of acinar cell apoptosis to the severity of acute pancreatitis.     

Protection against acute pancreatitis by activation of protease-activated receptor-2

Protease-activated receptor-2 (PAR-2) is a widely expressed tethered ligand receptor that can be activated by trypsin and other trypsin-like serine proteases. In the exocrine pancreas, PAR-2 activation modulates acinar cell secretion of digestive enzymes and duct cell ion channel function. During acute pancreatitis, digestive enzyme zymogens, including trypsinogen, are activated within the pancreas. We hypothesized that trypsin, acting via PAR-2, might regulate the severity of that disease, and to test this hypothesis, we examined the effect of either genetically deleting or pharmacologically activating PAR-2 on the severity of secretagogue-induced experimental pancreatitis. We found that experimental acute pancreatitis is more severe in PAR-2(-/-) than in wild-type mice and that in vivo activation of PAR-2, achieved by parenteral administration of the PAR-2-activating peptide SLIGRL-NH2, reduces the severity of pancreatitis. In the pancreas during the early stages of pancreatitis, the MAPK ERK1/2 is activated and translocated to the nucleus, but nuclear translocation is reduced by activation of PAR-2. Our findings indicate that PAR-2 exerts a protective effect on pancreatitis and that activation of PAR-2 ameliorates pancreatitis, possibly by inhibiting ERK1/2 translocation to the nucleus. Our observations suggest that PAR-2 activation may be of therapeutic value in the treatment and/or prevention of severe clinical pancreatitis, and they lead us to speculate that, from a teleological standpoint, PAR-2 may have evolved in the pancreas as a protective mechanism designed to dampen the injurious effects of intrapancreatic trypsinogen activation.     

TLR and MBL gene polymorphisms in severe acute pancreatitis

BACKGROUND AND OBJECTIVE: Mannose-binding lectin (MBL) and toll-like receptor (TLR)-4 gene polymorphisms have been implicated in inflammatory episodes in a number of studies. In view of the inflammatory nature of acute pancreatitis, we aimed to determine the predictive value of two point mutations in the promoter region at position -550 (H/L variants) and -221 (X/Y variants) of the MBL2 gene, and the Asp299Gly and 119C>A polymorphisms of the TLR4 gene on the occurrence of severe acute pancreatitis (SAP). METHODS: The study included 132 patients with SAP, 106 with mild acute pancreatitis (MAP), and 121 healthy volunteers. Genotypes were determined using restriction fragment length polymorphism analysis of PCR products and by allele-specific PCR. RESULTS: No significant difference in genotype frequency was noted between the patients with acute pancreatitis and controls for any of the gene loci studied. The distributions of the HY/HY, HY/LY, LY/LY, and LY/LX genotypes of MBL2 gene promoter and 119C>A genotype of the TLR4 gene were similar in patients with mild or severe acute pancreatitis. HY/LX genotype frequency was significantly higher in patients with SAP compared with MAP (26% vs 14%; p = 0.028). CONCLUSION: Results indicate that the MBL2 HY/LX genotype plays an important role in the determination of disease severity to acute pancreatitis.     

急性胰腺炎伴脾脏密度减低的研究现状

急性胰腺炎是临床上较常见的急腹症,以急性上腹痛和血尿淀粉酶或脂肪酶升高为其主要的临床特点,急性胰腺炎除了对胰腺自身组织的产生损伤外,对胰腺外器官也会产生不同的损伤,并引起一系列的并发症。在急性胰腺炎的脾脏并发症中,脾梗死在CT图像中表现为脾脏密度不均匀性减低,除此之外脾脏实质的密度在CT图像中是相对比较固定的,但是在有些急性胰腺炎患者的CT图像中会出现脾脏密度一过性弥漫性减低的影像表现,治疗后复查CT显示脾脏密度恢复正常,该现象的形成原因尚不清楚,国内外有关该现象的文献报道及研究十分的有限,本文通过分析急性胰腺炎的病因及发病机制,回顾相关的文献病例,探讨急性胰腺炎伴脾脏密度一过性弥漫性减低产生的可能性原因。     

不同评分标准对急性胰腺炎严重程度评估价值的比较

目的:分析和评价Ranson、Glasgow、APACHEⅡ和BISAP 4种临床评分标准对急性胰腺炎严重程度的评估价值。方法:回顾性研究急性胰腺炎患者225例,分别应用APACHEⅡ、Ranson、Glasgow及BISAP评分标准对急性胰腺炎患者进行评分,比较分析不同评分标准对该类患者诊断的敏感性、特异性,以及对合并脏器功能不全的预测情况。结果:225例患者中,轻型胰腺炎188例,重型胰腺炎37例,在轻型和重型胰腺炎患者中,4种评分标准分值差异均有统计学意义(P0.01)。47例患者存在器官功能不全,4种评分标准与患者合并脏器功能不全均显著相关。各评分标准中,APACHEⅡ对急性重症胰腺炎评估的敏感性、特异性最好,分别为76%和72%。结论:4中评分方法各有特点,综合应用可能更准确的评估疾病严重程度及预后。     

Apoptosis versus necrosis in acute pancreatitis

Acute pancreatitis is a disease of variable severity in which some patients experience mild, self-limited attacks, whereas others manifest a severe, highly morbid, and frequently lethal attack. The events that regulate the severity of acute pancreatitis are, for the most part, unknown. It is generally believed that the earliest events in acute pancreatitis occur within acinar cells and result in acinar cell injury. Other processes, such as recruitment of inflammatory cells and generation of inflammatory mediators, are believed to occur subsequent to acinar cell injury, and these "downstream" events are believed to influence the severity of the disease. Several recently reported studies, however, have suggested that the acinar cell response to injury may, itself, be an important determinant of disease severity. In these studies, mild acute pancreatitis was found to be associated with extensive apoptotic acinar cell death, whereas severe acute pancreatitis was found to involve extensive acinar cell necrosis but very little acinar cell apoptosis. These observations led to the hypothesis that apoptosis could be a favorable response to acinar cells and that interventions that favor induction of apoptotic, as opposed to necrotic, acinar cell death might reduce the severity of an attack of acute pancreatitis. Indeed, in an experimental setting, the induction of pancreatic acinar cell apoptosis protects mice against acute pancreatitis. Little is known about the mechanism of apoptosis in the pancreatic acinar cell, although some early attempts have been made in that direction. Also, clinical relevance of these experimental studies remains to be investigated.     

High concentrations of circulating interleukin-6 and monocyte chemotactic protein-1 with low concentrations of interleukin-8 were associated with severe chikungunya fever during the 2009-2010 outbreak in Thailand

The recent outbreak of Chikungunya virus in Thailand caused a rheumatic fever associated with considerable morbidity and fatalities. Thus, it is important to identify biomarker(s) of severe disease induced by this threatening arbovirus. Putative biomarkers in cases of chikungunya fever during an outbreak in the southern part of Thailand in 2009-2010 were identified. Sixty-two patients who had developed fever and myalgia, with or without arthralgia/arthritis, were enrolled and grouped into severe chikungunya fever (CHIKF) (n= 15), mild CHIKF (n= 20) and non-CHIKF (n= 27) to investigate circulating immunological mediators that might serve as markers of severity. Blood samples were taken at presentation (day 1) and 30 days later (day 30) and plasma concentrations of interleukin (IL)-1β, IL-6, IL-8, IL-17, tumor necrosis factor-alpha, monocyte chemotactic protein-1 (MCP-1), matrix metalloproteinase-1, tissue inhibitor of matrix metalloproteinase-1 and viral load were measured by ELISA. On day 1, severe CHIKF and mild CHIKF groups had viral loads of 10(8.5) and 10(8.3) of RNA copies/mL, respectively. At presentation, all CHIKF patients had circulating concentrations of IL-6 and MCP-1 higher than did non-CHIKF patients, whereas amongst the CHKF patients, the severe CHIKF patients had higher IL-6 concentrations than did mild CHIKF patients. Interestingly, severe CHIKF patients had significantly lower concentrations of circulating IL-8 than the other groups of patients, suggesting that high concentrations of IL-6 and MCP-1 with low concentrations of IL-8 may be a determinant of severe chikungunya virus infection.     

Pancreatic Duct Patterns in Acute Pancreatitis: A MRI Study

Objectives

To study the MRI findings of the pancreatic duct in patients with acute pancreatitis.

Materials and Methods

A total of 239 patients with acute pancreatitis and 125 controls were analyzed in this study. The severity of acute pancreatitis was graded using the MR severity index (MRSI) and the Acute Physiology And Chronic Healthy Evaluation II(APACHE II) scoring systems. The number of main pancreatic duct (MPD) segments visualized, and both MPD diameter and pancreatic duct disruption were noted and compared with the severity of acute pancreatitis.

Results

The frequency of MPD segment visualization in the control group was higher than that in the acute pancreatitis group (p<0.05). The number of MPD segments visualized was negatively correlated with the MRSI score (p<0.05) and the APACHE II score (p<0.05). There was no difference in the MPD diameter between the acute pancreatitis and control groups or among the patients with different severities of acute pancreatitis (p>0.05). The prevalence of pancreatic duct disruption was 7.9% in the acute pancreatitis group. The prevalences of pancreatic duct disruption were 4.8% and 15.3% in the mild and severe acute pancreatitis groups based on the APACHE II score, respectively, and were 0%, 5.7% and 43.5% in the mild, moderate and severe acute pancreatitis groups according the MRSI score, respectively. The prevalence of pancreatic duct disruption was correlated with the severity of acute pancreatitis based on the APACHE II score (p<0.05) and MRSI score (p<0.05).

Conclusion

The pancreatic duct in acute pancreatitis patients was of normal diameter. The number of MPD segments visualized and visible pancreatic duct disruption on MRI may be supplementary indicators for determining the severity of acute pancreatitis.     

Early assessment of severity of acute pancreatitis using peritoneal lavage.

Diagnostic peritoneal lavage using one litre of isotonic saline was performed on 27 patients with acute pancreatitis as soon as possible after diagnosis. There were no complications. Severe attacks (defined retrosepctively according to the progress of the attack) were characterised by the presence of free peritoneal fluid and by dark-coloured and often opalescent return fluid. The concentrations of albumin, aspartate aminotransferase (SGOT) and total protein in the return fluid provided good discrimination between severe and mild attacks, and there were also significant differences in the concentrations of amylase, urea, calcium, potassium, bilirubin, alkaline phosphatase, and the white cell count. Lavage successfully predicted severe disease in five patients whose condtion had been clinically assessed as mild.     

高脂血症性急性重症胰腺炎特征分析及治疗策略

目的:探讨高脂血症性急性重症胰腺炎(HSAP)患者的临床特点及诊疗分析,为急性重症胰腺炎(SAP)的诊治提供偱证依据。方法:回顾性分析了我科自2008年9月到2013年9月收治的101例急性胰腺炎患者血清脂肪酶、淀粉酶浓度、酶恢复时间、白细胞、甘油三酯差异以分析高脂血症性急性重症胰腺炎患者的病情转归情况。结果:HSAP患者甘油三酯(TG)水平男性明显高于女性,差异有统计学意义(P0.05);HSAP患者入院后经过降脂药物治疗HSAP与其他SAP相比较甘油三酯(TG)在短期内基本恢复正常,HSAP中白细胞、酶恢复时间低于其他SAP组,差异有统计学意义(P0.05);HSAP与高脂血症性急性轻型胰腺炎(HMAP)相比较两组间淀粉酶、脂肪酶、甘油三酯比较差异无统计学意义(P0.05),白细胞、酶恢复时间比较差异有统计学意义(P0.05)。结论:HSAP患者TG水平可能与患者的性别有一定的相关性;HSAP患者的病情转归可能与甘油三酯水平相关;甘油三酯水平不能直接决定高脂血症性急性胰腺炎患者病情的轻重。     

Clinical value of serum immunoreactive trypsin concentration.

The clinical value of estimation of serum concentrations of immunoreactive trypsin was evaluated by studying 46 healthy controls, 23 controls in hospital, 44 patients with chronic pancreatic disease, and 184 patients with non-pancreatic conditions in which pancreatic disease commonly enters into the differential diagnosis. Serum trypsin concentration had a log normal distribution in the controls, and the calculated normal range was considerably wider than that previously reported. The concentration was abnormal in only 13 out of 27 patients with chronic pancreatitis and was extremely variable in patients with pancreatic cancer. Abnormal results occurred in 11% of the patients with non-pancreatic disease. Eighteen patients had a subnormal trypsin concentration, of whom six did not have pancreatic disease and 12 had either chronic pancreatitis or pancreatic cancer. There was no correlation between serum trypsin concentration and mean tryptic activity as measured by the Lundh test. Of 11 patients with pancreatic steatorrhoea, only seven had subnormal trypsin concentrations. There results suggest that the serum concentrations of immunoreactive trypsin has a low specificity and sensitivity for pancreatic disease and does no reflect the degree exocrine insufficiency in patients with proved chronic pancreatitis.     

高脂血症性胰腺炎26例临床治疗分析

目的:分析26例高脂血症性胰腺炎的治疗及预后,探讨高脂血症性胰腺炎的治疗特点。方法:总结我科03．8-06．10间收治的高脂血症性胰腺炎病人26例的治疗及预后。结果:在高脂血症性胰腺炎26例,其中重症病例11例,重症病例中死亡二例,手术三例,合并糖尿病4例、合并高血压、冠心病5例,在所有高脂血症性胰腺炎中除重症中2例死亡外,其余根据胰腺炎的严重程度不同采用相应的治疗办法而全部治愈。结论:高脂血症性胰腺炎的发病率相对较高,其并发病多、死亡率高,治疗以降血脂为主的多方位的综合治疗,血液净化是重症高脂血症性胰腺炎早期治疗一种较有用的方式。     

Is nasogastric suction necessary in acute pancreatitis?

Fifty-eight patients with mild to moderately severe acute pancreatitis were randomly allocated to treatment with or without nasogastric suction (27 and 31 patients respectively). Intravenous fluids and pethidine hydrochloride were also given. The two groups were comparable clinically at the start of the study. There were no differences between the two groups in the mean duration of the following features: abdominal pain or tenderness; absence of bowel movements; raised serum amylase concentration; time to resumption of oral feeding; and days in hospital. Prolonged hyperamylasaemia (serum amylase greater than 0.33 mU/l) occurred in one patient in the suction group and in three patients in the non-suction group. A mild recurrence of abdominal pain after resumption of oral feeding occurred in three patients in the suction group and in two patients in the non-suction group. Two patients in the suction group developed overt consumption coagulopathy and two others pulmonary complications. No patient in the non-suction group had complications. The findings suggest that most patients with mild to moderately severe acute pancreatitis do not benefit from nasogastric suction. The procedure should be elective rather than mandatory in treating this condition.     

Activation of the complement cascade by trypsin

In twenty-three patients with acute pancreatitis, the plasma levels of immunoreactive trypsin were determined with a RIA method. The patients were divided into groups according to the severity of the disease. Ranson's criteria and the development of multisystem organ failure were used for the classification. Elevated plasma levels of immunoreactive trypsin were found in all groups after admittance. Incubation of fresh human serum and plasma with bovine trypsin in concentrations between 10(-6) and 10(-4) M at 20 degrees C activated the complement cascade. The anaphylatoxins C3a and C5a were determined with a RIA and the terminal complement complex (TCC) with an ELISA method. C3a and C5a were released and TCC was formed. The effect of trypsin on leukocyte activation was determined with a chemiluminescence technique. Trypsin dissolved in saline did not activate the leukocytes. However, serum digested by trypsin-activated leukocytes in a dose-dependent manner. The present study supports the theory that trypsin can activate complement components and results in formation of split products which have potent vascular, and leukocyte activating effects.     

急性胰腺炎患者胃肠动力紊乱与胃肠激素的关系分析

目的:探讨急性胰腺炎(AP)患者的胃肠动力紊乱与胃肠激素的关系。方法:收集2014年3月~2015年4月我院消化科收治的90例AP患者为病例组,按病情严重程度分为轻症急性胰腺炎组(MAP组,39例)、中重症急性胰腺炎组(MSAP组,33例)及重症急性胰腺炎组(SAP组,18例),并于同期抽取30例健康体检者作为对照组,通过采用双抗体夹心酶联免疫法(ELASA)测量入院第1、3、7天的血清胃动素(MTL)、血管活性肠肽(VIP)在各组中的水平,同时测量口盲传递时间(OCTT)来衡量AP的严重程度。结果:MAP组、MSAP组及SAP组血清MTL水平均较对照组明显降低,且随着入院治疗时间的延长逐渐升高,差异均有统计学意义(P0.05)。MAP组、MSAP组及SAP组血清VIP水平均较对照组明显升高,且随着入院治疗时间的延长逐渐降低,差异均有统计学意义(P0.05)。血清MTL水平与OCTT呈负相关性(rs=-0.534、-0.629、-0.468,P0.05);血清VIP水平与OCTT呈正相关性(rs=0.464、0.326、0.671,P0.05)。结论:胃肠动力紊乱可能与胃肠激素异常有关,表现为MTL水平降低、VIP水平升高,且其改变幅度与病情的严重程度相一致。     

Is fatal pancreatitis a consequence of excessive leukocyte stimulation? The role of tumor necrosis factor alpha

This study examines the possible role of excessive leukocyte stimulation in the pathogenesis of acute pancreatitis. Levels of tumor necrosis factor alpha (TNF-alpha) and elastase-alpha 1 proteinase inhibitor (E-alpha 1PI) have been measured as markers of macrophage and neutrophil activation, respectively, in serial plasma samples from 27 patients with acute pancreatitis. Levels of TNF-alpha did not support the possibility of excessive macrophage activation, but raised levels of E-alpha 1PI in patients with either the mild or severe form of the illness indicated the activation of neutrophils. Whether this is a consequence of the illness or is a contributory factor in the pathogenesis is not clear.     

Perfusion-CT - Can We Predict Acute Pancreatitis Outcome within the First 24 Hours from the Onset of Symptoms?

Purpose

Severe acute pancreatitis (AP) is still a significant clinical problem which is associated with a highly mortality. The aim of this study was the evaluation of prognostic value of CT regional perfusion measurement performed on the first day of onset of symptoms of AP, in assessing the risk of developing severe form of acute pancreatitis.

Material and Methods

79 patients with clinical symptoms and biochemical criteria indicative of acute pancreatitis (acute upper abdominal pain, elevated levels of serum amylase and lipase) underwent perfusion CT within 24 hours after onset of symptoms. The follow-up examinations were performed after 4–6 days to detect progression of the disease. Perfusion parameters were compared in 41 people who developed severe form of AP (pancreatic and/or peripancreatic tissue necrosis) with parameters in 38 consecutive patients in whom course of AP was mild. Blood flow, blood volume, mean transit time and permeability surface area product were calculated in the three anatomic pancreatic subdivisions (head, body and tail). At the same time the patient''s clinical status was assessed by APACHE II score and laboratory parameters such as CRP, serum lipase and amylase, AST, ALT, GGT, ALP and bilirubin were compared.

Results

Statistical differences in the perfusion parameters between the group of patients with mild and severe AP were shown. Blood flow, blood volume and mean transit time were significantly lower and permeability surface area product was significantly higher in patients who develop severe acute pancreatitis and presence of pancreatic and/or peripancreatic necrosis due to pancreatic ischemia. There were no statistically significant differences between the two groups in terms of evaluated on admission severity of pancreatitis assessed using APACHE II score and laboratory tests.

Conclusions

CT perfusion is a very useful indicator for prediction and selection patients in early stages of acute pancreatitis who are at risk of developing pancreatic and/or peripancreatic necrosis already on the first day of the onset of symptoms and can be used for treatment planning and monitoring of therapy of acute pancreatitis. Early suspicion of possible pancreatic necrosis both on the basis of scores based on clinical status and laboratory tests have low predictive value.