Diabetes mellitus and the exocrine pancreas

Diabetes and carbohydrate intolerance can occur in pancreatitis. Although one-half of patients with acute pancreatitis will have some evidence of glucose intolerance during their acute illness, few will require insulin administration on either a short- or long-term basis. The diabetes seen in acute pancreatitis is likely due to a combination of factors, including alerted insulin secretion, increased glucagon release, and decreased glucose utilization by the liver and peripheral tissue. Chronic pancreatitis is often associated with diabetes mellitus, with the incidence as high as 70 percent when pancreatic calcification is present. These patients tend to be very sensitive to the effects of insulin and hypoglycemia. This is probably secondary to concurrent hepatic disease, malnutrition, and a relative decrease in glucagon reserves. The diabetes seen in chronic pancreatitis is associated with decreased insulin production. Finally, although the endocrine pancreas may influence the exocrine gland through a portal system, primary diabetes mellitus probably does not result in clinically significant alterations in pancreatic exocrine function.     

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。     

乌司他丁治疗不同类型急性胰腺炎的临床疗效

目的:探讨乌司他丁用于治疗不同类型急性胰腺炎的临床疗效和安全性。方法:收集2013年1月至2014年1月我院收治的急性胰腺炎患者84例,随机分为观察组与对照组,每组各42例,两组患者均给予常规治疗,对照组加用奥曲肽治疗,观察组在对照组的基础上加用乌司他丁治疗,观察和比较两组患者的临床疗效、治疗前后血清IL-6和TNF-α水平的变化及不良反应的发生情况。结果:观察组的总有效率为96.72%,显著高于对照组的85.71%;其中,两组急性水肿型胰腺炎的疗效相当(P0.05),但观察组出血坏死型胰腺炎的有效率显著高于对照组(P0.05)。治疗后,两组血清IL-6与TNF-α水平均较治疗前显著降低,并且观察组显著低于对照组(P0.05),水肿型胰腺炎患者血清IL-6及TNF-α水平显著低于出血坏死型胰腺炎患者,差异均具有统计学意义(P0.05)。两组均未发生肝肾功能损害,未见药物相关性不良反应。结论:乌司他丁用于辅助治疗急性胰腺炎能够明显下调炎症因子水平,临床疗效显著,对急性水肿型胰腺炎的疗效尤为显著,安全性好,值得推广应用。     

Impact of Global Fxr Deficiency on Experimental Acute Pancreatitis and Genetic Variation in the FXR Locus in Human Acute Pancreatitis

Background

Infectious complications often occur in acute pancreatitis, related to impaired intestinal barrier function, with prolonged disease course and even mortality as a result. The bile salt nuclear receptor farnesoid X receptor (FXR), which is expressed in the ileum, liver and other organs including the pancreas, exhibits anti-inflammatory effects by inhibiting NF-κB activation and is implicated in maintaining intestinal barrier integrity and preventing bacterial overgrowth and translocation. Here we explore, with the aid of complementary animal and human experiments, the potential role of FXR in acute pancreatitis.

Methods

Experimental acute pancreatitis was induced using the CCK-analogue cerulein in wild-type and Fxr^-/- mice. Severity of acute pancreatitis was assessed using histology and a semi-quantitative scoring system. Ileal permeability was analyzed in vitro by Ussing chambers and an in vivo permeability assay. Gene expression of Fxr and Fxr target genes was studied by quantitative RT-PCR. Serum FGF19 levels were determined by ELISA in acute pancreatitis patients and healthy volunteers. A genetic association study in 387 acute pancreatitis patients and 853 controls was performed using 9 tagging single nucleotide polymorphisms (SNPs) covering the complete FXR gene and two additional functional SNPs.

Results

In wild-type mice with acute pancreatitis, ileal transepithelial resistance was reduced and ileal mRNA expression of Fxr target genes Fgf15, SHP, and IBABP was decreased. Nevertheless, Fxr^-/- mice did not exhibit a more severe acute pancreatitis than wild-type mice. In patients with acute pancreatitis, FGF19 levels were lower than in controls. However, there were no associations of FXR SNPs or haplotypes with susceptibility to acute pancreatitis, or its course, outcome or etiology.

Conclusion

We found no evidence for a major role of FXR in acute human or murine pancreatitis. The observed altered Fxr activity during the course of disease may be a secondary phenomenon.     

Management of necrotizing pancreatitis.

A comprehensive management plan is presented for patients with severe acute pancreatitis. These patients may have pancreatic or peripancreatic necrosis or pancreatic fluid collections. Multiple organ failure often develops in patients with severe pancreatitis. We therefore recommend that all patients with acute pancreatitis be evaluated for pancreatic anatomy and function. If a patient is seriously ill, a computed tomographic (CT) scan with vascular enhancement should be done. Meanwhile, vigorous fluid replacement is necessary using Swan-Ganz monitoring. Patients with necrosis do not need surgical intervention unless the clinical course or CT scan-guided aspiration shows infection. The objective of an operation should be to remove all infected tissue and fluid. A preoperative CT scan with vascular enhancement should be used as a guide during the operation to ensure that all foci of infected necrosis or fluid are eliminated. We have found that open packing and irrigation with sodium oxychlorosene are helpful in patients with extensive necrosis or those who become infected early after the onset of symptoms. In all, 40% to 50% of patients treated by closed drainage will require reoperation because of incomplete debridement. Persistent sepsis is an indication for reoperation.     

Insulin sensitivity in pancreatitis, liver diseases, steroid treatment and hyperthyroidism assessed by glucose, insulin and somatostatin infusion

In order to assess insulin sensitivity for glucose utilization in the other type of diabetes, insulin sensitivity tests were performed in subjects with pancreatitis, liver disease, steroid treatment and hyperthyroidism. Insulin sensitivity for glucose utilization decreased in subjects with liver disease, steroid treatment and hyperthyroidism irrespective of the presence or absence of glucose intolerance. Hyperinsulinism was associated in most of the subjects with liver disease and steroid treatment, but even in normo-insulinemic subjects, insulin insensitivity was observed. Obesity was associated with only 2 cases in both pancreatitis and liver diseases and therefore was excluded as a major cause for insulin insensitivity in subjects studied. In subjects with pancreatitis, insulin sensitivity was not significantly decreased. It is to be noted that 4 out of 5 subjects with diabetic OGTT (oral glucose tolerance test) exhibited normal insulin sensitivity. The results indicate that in pancreatitis, tissue insulin sensitivity for glucose metabolism is not altered and therefore can be used as a marker to differentiate the other type of diabetes due to pancreatitis from type 1 or 2 diabetes. Although hyperinsulinemia may be attributable to insulin insensitivity in subjects studied at least in part, steroid and thyroid hormone are thought to act directly antagonistically with insulin for glucose metabolism.     

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.     

ACUTE PANCREATITIS

Pain, and nausea and vomiting are the two cardinal symptoms of acute pancreatitis.There are variations in the combinations of symptoms that appear in patients who have acute pancreatitis, but in most cases the combination fits one or another of five classifications.Blood amylase and urinary diastase determinations are valuable aids in the diagnosis of acute pancreatitis. These findings must be correlated with the stage of the disease.As the disease may be treated successfully (by means outlined) without surgical intervention, clinical diagnosis is important.Cholecystograms after an attack of acute pancreatitis, although advisable, should not be made too soon after subsidence, because of the danger of exacerbation.     

Nutrición basada en la evidencia en la pancreatitis aguda y la enfermedad hepática crónica estable

Acute pancreatitis is a disease that, by definition, generates an increase in metabolism. This metabolic reaction, together with the anorexia produced by the disease, clearly increases morbidity and mortality secondary to malnutrition.Malnutrition affects almost 70% of patients with cirrhosis, with a consequent increase in complications. The present review aims to evaluate the utility of the use of total parenteral nutrition (TPN) and/or enteral nutrition (EN) in patients with acute pancreatitis and in those with stable chronic liver disease.In patients with acute pancreatitis, the administration of enteral nutrition seems to confer advantages over parenteral nutrition in clinical variables (infections, surgical interventions, and mean length of hospital stay) (A-B); nevertheless, further studies stratifying patients according to the severity of pancreatitis and probably its etiology should be designed. Glutamine supplementation can be effective in reducing length of hospital stay and duration of nutritional support (B).In patients with stable chronic liver disease, there are no studies that demonstrate the superiority of EN over PN, or vice versa, in relevant clinical variables (mortality, length of hospital stay, etc.). There is only one study that has demonstrated that EN is superior to oral intake in reducing mortality (B).Improved study designs and the need to perform studies according to the type and severity of liver disease should be a research priority.     

Acute pancreatitis

Pain, and nausea and vomiting are the two cardinal symptoms of acute pancreatitis. There are variations in the combinations of symptoms that appear in patients who have acute pancreatitis, but in most cases the combination fits one or another of five classifications. Blood amylase and urinary diastase determinations are valuable aids in the diagnosis of acute pancreatitis. These findings must be correlated with the stage of the disease. As the disease may be treated successfully (by means outlined) without surgical intervention, clinical diagnosis is important. Cholecystograms after an attack of acute pancreatitis, although advisable, should not be made too soon after subsidence, because of the danger of exacerbation.     

Prediction of gall-stone pancreatitis by computer.

The clinical features at presentation of 53 patients admitted with primary acute pancreatitis due to gall stones were compared with those of 31 patients in whom the disease was due to other causes. Between these two groups 10 significant differences existed. By listing the frequency of symptoms and signs for each group a computer data base was prepared and incorporated into a program used in the differential diagnosis of acute abdominal pain. A program written to predict the presence of gall stones in patients with acute pancreatitis was accurate in 92% of the patients studied. A predictive index devised from the presence of three of the significantly differing clinical features correctly identified 82% of patients with gall-stone pancreatitis. Predicting the presence of gall stones on admission by analysing the presenting symptoms and signs with a computer had an accuracy comparable to that of ultrasonography or radiology and may be of value in the management of patients with acute pancreatitis.     

肠道菌群与乙型肝炎病毒感染相关肝病的研究进展

乙型肝炎病毒(hepatitis B virus, HBV)可引起人体急性或慢性感染,甚至导致肝硬化或肝癌,其作用机制目前仍未完全阐明。近年来,肠-肝轴受到广泛关注,肠道微生态的相关研究迅速发展,越来越多的实验结果表明,肠道菌群(gut microbiota, GM)与HBV相关肝病的发生和发展具有一定关联。GM可能是了解HBV感染发病机制的一个新视角,并为HBV相关疾病的治疗提供新靶点,这将对未来的治疗策略产生积极影响。本文就HBV感染者肠道菌群与乙型肝炎相关肝病的研究进展进行综述。     

Induction of M2 Polarization in Primary Culture Liver Macrophages from Rats with Acute Pancreatitis

Background and Aims

Systemic inflammatory response syndrome (SIRS), a major process of severe acute pancreatitis (SAP), usually occurs after various activated proinflammatory cytokines, which are produced by macrophages such as liver macrophages. Macrophages can secrete not only proinflammatory mediators but also inhibitory inflammatory cytokines such as IL-10, leading to two different functional states defined as “polarization”. The main purpose of this study was to demonstrate the polarization of liver macrophages during severe acute pancreatitis and to explore whether the polarization of these activated Liver macrophages could be reversed in vitro.

Methods

Liver macrophages were isolated from rats with acute pancreatitis. These primary culture macrophages were treated with IL-4 or regulatory T cells in vitro to reverse their polarization and was evaluated by measuring M1/M2 marker expression using real time PCR and immunofluorescence staining.

Results

Acute pancreatitis was induced successfully by intra-pancreatic ductal injection of 5% sodium taurocholate. The liver macrophages demonstrated M1 polarization from 4 h to 16 h after the onset of acute pancreatitis. However, after IL-4 or Treg treatment, the polarization of the liver macrophages was reversed as indicated by increased expression of M2 markers and reduced expression of M1 markers. Furthermore, the effect of Treg on modulating macrophage polarization was slightly better than that of IL-4 in vitro.

Conclusion

Liver macrophages, a pivotal cell type in the pathogenesis of SAP, become M1 polarized during pancreatic inflammation. Treatment of these cells with IL-4 and Treg can reverse this activation in vitro. This method of altering macrophage polarization could be a prospective therapy for SAP.     

A complicated pregnancy in a patient with lipodystrophic diabetes attributable to a peroxisome proliferator-activated receptor gamma (PPARG) mutation

Diabet. Med. 29, e398-e401 (2012) ABSTRACT: Background We describe an unplanned pregnancy in a 19-year-old with lipodystrophic diabetes caused by a mutation in the peroxisome proliferator-activated receptor gamma (PPARG) gene. The pregnancy was complicated by poor compliance with treatment, severe hypertriglyceridaemia and pancreatitis. Case report The patient presented at 6?weeks' gestation with an HbA(1c) of 140?mmol/mol (15%), cholesterol 8.1?mmol/l and triglycerides 20.1?mmol/l. She wished to continue the pregnancy so lipid-lowering therapy was discontinued. She was severely insulin resistant and poorly compliant with diet and medication. A continuous subcutaneous insulin infusion was required for efficient delivery of large doses of basal insulin, alongside injected mealtime boluses, (up to 300?units insulin per day). At 17?weeks' gestation she developed acute pancreatitis secondary to hypertriglyceridaemia (triglycerides >?100?mmol/l) and required plasmapheresis. Lipid-lowering therapy was reinstated in the third trimester and plasmapheresis was required repeatedly to maintain triglycerides 相似文献   

Pancreatic response to endotoxin after chronic alcohol exposure: switch from apoptosis to necrosis?

Chronic alcohol consumption is known to increase the susceptibility to acute and chronic pancreatitis, and it is likely that a cofactor is required to initiate the progression to alcoholic pancreatitis. The severity and complications of alcoholic and nonalcoholic acute pancreatitis may be influenced by a number of cofactors, including endotoxemia. To explore the effect of a possible cofactor, we used endotoxin [lipopolysaccharide (LPS)] as a tool to induce cellular injury in the alcoholic pancreas. Single, increasing doses of endotoxin were injected in rats fed an alcohol or control diet and killed 24 h after the injection. We examined the mechanism by which LPS exacerbates pancreatic injury in alcohol-fed rats and whether the injury is associated with apoptosis or necrosis. We showed that chronic alcohol exposure alone inhibits apoptosis through the intrinsic pathway and the downstream apoptosis executor caspase-3 compared with the controls. Pancreatic necrosis and inflammation increased after LPS injection in control and alcohol-fed rats in a dose-dependent fashion but with a significantly greater response in the alcohol-fed animals. Caspase activities and TdT-mediated dUTP nick-end labeling positivity were lower in the alcoholic pancreas injected with LPS, whereas the histopathology and inflammation were more severe compared with the control-fed animals. Assessment of a putative indicator of necrosis, the ratio of ADP to ATP, indicated that alcohol exposure accelerates pancreatic necrosis in response to endotoxin. These findings suggest that the pancreas exposed to alcohol is more sensitive to LPS-induced damage because of increased sensitivity to necrotic cell death rather than apoptotic cell death. Similar to the liver, the pancreas is capable of responding to LPS with a more severe response in alcohol-fed animals, favoring pancreatic necrosis rather than apoptosis. We speculate that this mechanism may occur in acute alcoholic pancreatitis patients.     

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。     

Low intracellular magnesium in patients with acute pancreatitis and hypocalcemia.

To determine the role of magnesium deficiency in the pathogenesis of hypocalcemia in acute pancreatitis, we measured magnesium levels in serum and in peripheral blood mononuclear cells in 29 patients with acute pancreatitis, 14 of whom had hypocalcemia and 15 of whom had normal calcium levels. Only six patients had overt hypomagnesemia (serum magnesium less than 0.70 mmol per liter [1.7 mg per dl]). The mean serum magnesium concentration in hypocalcemic patients was not significantly lower than in normocalcemic patients, but the mononuclear cell magnesium content in hypocalcemic patients with pancreatitis was significantly lower than in normocalcemic patients with pancreatitis (P less than .01). The serum magnesium level did not correlate with that of serum calcium or the mononuclear cell magnesium content, but the latter did significantly correlate with the serum calcium concentration (r = .81, P less than .001). Most patients with hypocalcemia had a low intracellular magnesium content. Three normomagnesemic, hypocalcemic patients with alcoholic pancreatitis also underwent low-dose parenteral magnesium tolerance testing and showed increased retention of the magnesium load. We conclude that patients with acute pancreatitis and hypocalcemia commonly have magnesium deficiency despite normal serum magnesium concentrations. Magnesium deficiency may play a significant role in the pathogenesis of hypocalcemia in patients with acute pancreatitis.     

BPC 157 therapy to detriment sphincters failure-esophagitis-pancreatitis in rat and acute pancreatitis patients low sphincters pressure

Possibly, acute esophagitis and pancreatitis cause each other, and we focused on sphincteric failure as the common causative key able to induce either esophagitis and acute pancreatitis or both of them, and thereby investigate the presence of a common therapy nominator. This may be an anti-ulcer pentadecapeptide BPC 157 (tested for inflammatory bowel disease, wound treatment) affecting esophagitis, lower esophageal and pyloric sphincters failure and acute pancreatitis (10 μg/kg, 10 ng/kg intraperitoneally or in drinking water). The esophagitis-sphincter failure procedure (i.e., insertion of the tubes into the sphincters, lower esophageal and pyloric) and acute pancreatitis procedure (i.e., bile duct ligation) were combined in rats. Esophageal manometry was done in acute pancreatitis patients. In rats acute pancreatitis procedure produced also esophagitis and both sphincter failure, decreased pressure 24 h post-surgery. Furthermore, bile duct ligation alone immediately declines the pressure in both sphincters. Vice versa, the esophagitis-sphincter failure procedure alone produced acute pancreatitis. What's more, these lesions (esophagitis, sphincter failure, acute pancreatitis when combined) aggravate each other (tubes into sphincters and ligated bile duct). Counteraction occurred by BPC 157 therapies. In acute pancreatitis patients lower pressure at rest was in both esophageal sphincters in acute pancreatitis patients. We conclude that BPC 157 could cure esophagitis/sphincter/acute pancreatitis healing failure.     

Hsp72 overexpression accelerates the recovery from caerulein-induced pancreatitis

Background and Aims

Heat shock protein (Hsp) 72 is a molecular chaperone which is upregulated in response to a variety of stress situations and has a general cytoprotective function. Increased Hsp72 levels were implicated in protection from acute pancreatitis; a hypothesis which was not tested in a transgenic mouse model yet.

Methods

To analyze the role of Hsp72 during acute pancreatitis, well-characterized transgenic animals overexpressing rat Hsp72 (Hsp72 mice) under the control of the ß-actin promoter were subjected to caerulein- and L-arginine-induced acute pancreatitis. The severity of experimental pancreatitis was determined via serum lipase levels, morphometric evaluation and quantification of pancreatic edema/inflammation.

Results

Hsp72 mice displayed ∼100-times Hsp72 overexpression, but no changes in the remaining chaperones. Robust Hsp72 signal was observed in pancreatic acini, but not in islets or ductal cells. In both models, elevated Hsp72 did not protect from development of acute pancreatitis and the pancreatitis-associated lung injury, but accelerated recovery from caerulein-induced tissue injury (lower lipase levels, edema, inflammation and necrosis 36 h after caerulein administration). The observed protective function of Hsp72 in caerulein-induced pancreatitis is likely due to an attenuated NF-κB signalling.

Conclusions

Hsp72 overexpression accelerates the recovery from acute pancreatitis and may represent a potential treatment strategy.