Genetic susceptibility factors for alcohol-induced chronic pancreatitis.

Chronic pancreatitis is a progressive inflammatory disease of the pancreas and frequently associated with immoderate alcohol consumption. Since only a small proportion of alcoholics eventually develop chronic pancreatitis genetic susceptibility factors have long been suspected to contribute to the pathogenesis of the disease. Smaller studies in ethnically defined populations have found that not only polymorphism in proteins involved in the metabolism of ethanol, such as Alcohol Dehydrogenase and Aldehyde Dehydrogenase, can confer a risk for developing chronic pancreatitis but also mutations that had previously been reported in association with idiopathic pancreatitis, such as SPINK1 mutations. In a much broader approach employing genome wide search strategies the NAPS study found that polymorphisms in the Trypsin locus (PRSS1 rs10273639), and the Claudin 2 locus (CLDN2-RIPPLY1-MORC4 locus rs7057398 and rs12688220) confer an increased risk of developing alcohol-induced pancreatitis. These results from North America have now been confirmed by a European consortium. In another genome wide approach polymorphisms in the genes encoding Fucosyltransferase 2 (FUT2) non-secretor status and blood group B were not only found in association with higher serum lipase levels in healthy volunteers but also to more than double the risk for developing alcohol-associated chronic pancreatitis. These novel genetic associations will allow to investigate the pathophysiological and biochemical basis of alcohol-induced chronic pancreatitis on a cellular level and in much more detail than previously possible.

Activity of neutrophil elastase reflects the progression of acute pancreatitis.

OBJECTIVE: Neutrophil elastase (NE) concentration is associated with progression of acute pancreatitis (AP), but measuring total NE concentration includes biologically inactive NE. This study aims to investigate the relationship between NE activity and the aetiology and severity of AP and associated organ failure. METHODS: Seventy-five patients admitted to our surgery department with a first episode of AP during 2004-2005 were age- and sex-matched to 20 healthy volunteers (controls). NE activity was assessed using venous blood samples obtained on patient admission and after 1, 2 and 14 days. One sample was also taken from each control. ANOVA was used for statistical comparison between groups. RESULTS: Baseline NE activity (geometric mean; 95% confidence intervals) differed between patients (58.6 nM of substrate 7-amino-4-methylcoumarin [AMC]/hour; 48.52-70.72) and controls (31.5 nM AMC/hour; 25.5-39.0) (p = 0.0003), and did not correlate with time between symptom onset and admission. Patients with alcohol-induced AP demonstrated higher mean activity (59.1 nM AMC/h; 44.7-78.2) than those with gallstone-induced AP (41.7 nM AMC/h; 33.9-51.4) (p = 0.0496). NE activity was higher overall in patients with predicted severe AP (60.9 nM AMC/h; 48.0-77.2) than in those with predicted mild AP (42.1 nM AMC/h; 34.9-50.8) (p = 0.027). Patients with respiratory failure had higher NE activity (82.5 nM AMC/h; 57.5-118.4) than those without (43.9 nM AMC/h; 37.6-51.3) (p = 0.0024). CONCLUSIONS: NE activity was associated with predicted severity of AP and AP-associated respiratory failure. Specific NE inhibitors may have therapeutic potential in acute pancreatitis.

Preventive role of gallic acid on alcohol dependent and cysteine protease-mediated pancreas injury.

In order to investigate an association between alcohol consumption and lysosomal cysteine protease induced pancreatic injury and preventive effect of gallic acid as dose-dependent, we determined myeloperoxidase and malondialdehyde levels, serum amylase activities and cathepsin B and L activities in the cytosolic and lysosomal fractions of pancreatic tissue in the ethanol (8 g/kg) and ethanol plus gallic acid (at different doses 50, 100 and 200 mg/kg) given rats. Absolute ethanol (8 g/kg) was given by oral gavage. Gallic acid was dissolved in the saline (2 ml/kg) and administered before 30 min the oral administration of ethanol. Pancreatic myeloperoxidase and also malondialdehyde levels and serum amylase activities were measured. Besides, histological investigations were made. Cathepsin B activities in the cytosolic fraction were decreased by gallic acid (200 mg/kg) and increased in ethanol given rats. Cytosolic/lysosomal ratio of cathepsin B and L were found to be low in the all doses of gallic acid as compared to ethanol group. Serum amylase, pancreatic myeloperoxidase activities and malondialdehyde levels in the ethanol group were higher than in the control group. These were not statistically significant for myeloperoxidase and malondialdehyde. Also, our histopathologic results indicated that ethanol administration increased pancreatic tissue injury. Gallic acid especially at 200 mg/kg improved ethanol-mediated pancreatic tissue damage.In conclusion, gallic acid treatments were decreased release of lysosomal cathepsin B and L enzymes into cytoplasmic fraction and prevented alcohol mediated pancreatic tissue injury. Preventive effect of gallic acid might be dose-dependent.

The N34S mutation of the SPINK1 gene and alcoholic chronic pancreatitis.

INTRODUCTION:  Recent studies have shown the key role of genetic factors in the development of chronic pancreatitis. OBJECTIVES:  The aim of the study was to establish whether the frequency of the N34S mutation of serine protease inhibitor Kazal type 1 (SPINK1) gene differs between patients with alcoholic chronic pancreatitis, patients with nonalcoholic chronic pancreatitis, alcoholics without any digestive organ damage, and controls. We also sought to investigate whether the frequency of this mutation differs between women and men, and whether the mutation is associated with the age of patients at first diagnosis of chronic pancreatitis. PATIENTS AND METHODS:  The study included 207 patients: 67 with alcoholic chronic pancreatitis, 35 with nonalcoholic chronic pancreatitis, 43 alcoholics with no damage to digestive organs, and 62 healthy volunteers who served as controls. The N34S mutation of the SPINK1 gene was detected with the polymerase chain reaction. RESULTS:  The N34S mutation of the SPINK1 gene occurred in 15 of 207 patients (7.25%). The mutation was most frequent in patients with alcoholic chronic pancreatitis (10 patients, 16.39%) and was more frequent compared with the control group (2 patients, 3.23%) (P = 0.047). There were no statistically significant differences between the other groups: patients with nonalcoholic chronic pancreatitis (2 patients, 5.71%), alcoholics without digestive organ damage (1 patient, 2.33%), and controls. The mutation was more frequent in men than in women (P = 0.043). There were no differences between patients with and without the mutation in terms of the age at first diagnosis of chronic pancreatitis (P >0.05). CONCLUSIONS:  The N34S mutation of the SPINK1 gene seems to be significantly correlated with alcoholic chronic pancreatitis.

Effects of ethanol metabolites on exocytosis of pancreatic acinar cells in rats.

BACKGROUND & AIMS: During development of alcoholic pancreatitis, oxidative (acetaldehyde) and nonoxidative metabolites (ethyl palmitate, ethyl oleate), rather than ethanol itself, mediate toxic injury. Exposure of pancreatic acini to ethanol blocks cholecystokinin (CCK)-8-stimulated apical exocytosis and redirects exocytosis to the basolateral plasma membrane, causing interstitial pancreatitis. We examined how each ethanol metabolite contributes to these changes in exocytosis. METHODS: Rat pancreatic acini were incubated with concentrations of ethanol associated with alcoholic pancreatitis (20-50 mmol/L) or ethanol metabolites (1-3 mmol/L) and then stimulated with CCK-8. We performed single zymogen granule (ZG) exocytosis assays, Ca(2+) imaging studies, ultrastructural analyses (with electron microscopy), and confocal microscopy to assess the actin cytoskeleton and track the movement of vesicle-associated membrane protein (VAMP)-8-containing ZGs. Coimmunoprecipitation assays were used to identify complexes that contain the distinct combinations of Munc18 and the soluble N-ethylmaleimide sensitive factor attachment protein receptor proteins, which mediate apical (ZG-apical plasma membrane) and basolateral exocytosis and fusion between ZGs (ZG-ZG). RESULTS: The ethanol metabolites acetaldehyde, ethyl palmitate, and ethyl oleate reduced CCK-8-stimulated apical exocytosis and formation of apical exocytotic complexes (between Munc18b and Syntaxin-2, synaptosomal-associated protein of 23 kilodaltons [SNAP23], and VAMP2) in rat pancreatic acini. Acetaldehyde and ethyl oleate redirected CCK-8-stimulated exocytosis to the basal and lateral plasma membranes and translocation of VAMP8-containing ZGs toward the basolateral plasma membrane. This process was mediated primarily via formation of basolateral exocytotic complexes (between Munc18c and Syntaxin-4, SNAP23, and VAMP8). Exposure of the acini to acetaldehyde and ethyl oleate followed by CCK-8 stimulation mildly perturbed the actin cytoskeleton and Ca(2+) signaling; exposure to ethyl palmitate severely affected Ca(2+) signaling. Acetaldehyde, like ethanol, promoted fusion between ZGs by the formation of ZG-ZG exocytotic complexes (between Munc18b and Syntaxin-3, SNAP23, and VAMP8), whereas ethyl palmitate and ethyl oleate reduced ZG-ZG fusion and formation of these complexes. CONCLUSIONS: The ethanol metabolites acetaldehyde, ethyl palmitate, and ethyl oleate perturb exocytosis processes in cultured rat pancreatic acini (apical blockade, basolateral exocytosis, and fusion between ZGs). Acetaldehyde and, to a lesser degree, ethyl oleate produce many of the same pathologic effects of ethanol on CCK-8-stimulated exocytosis in pancreatic acini.

Mannan-binding lectin and mannan-binding lectin-associated serine protease 2 in acute pancreatitis.

OBJECTIVES: Complement activation may play a prominent role in acute pancreatitis (AP). Mannan-binding lectin (MBL) and MBL-associated serine protease 2 (MASP-2) participate in complement activation. The objective of the present study was to evaluate the role of MBL and MASP-2 as markers in AP with regard to etiology, inflammatory activity, severity, and development of multiorgan failure. METHODS: Sixty patients with AP were included. All patients were diagnosed and treated according to a standardized regimen. Blood samples were obtained immediately on admission and again on days 1, 2, and 14. RESULTS: Both MBL (P < 0.001) and MASP-2 (P = 0.002) levels changed significantly over time, but without any significant relation to severity, multiorgan failure, or mortality. We found significantly higher levels of MBL (P = 0.04) in alcohol- than in gallstone-induced AP, but no significant difference in MASP-2 levels. CONCLUSIONS: The MBL and MASP-2 acted as acute-phase reactants, but overall, they were not markers for severity, multiorgan failure, nor for mortality in AP. Our results suggest that MBL and MASP-2 play only a minor role in the inflammatory response in AP.

Pancreatic injury in hepatic alcohol dehydrogenase-deficient deer mice after subchronic exposure to ethanol.

Pancreatitis caused by activation of digestive zymogens in the exocrine pancreas is a serious chronic health problem in alcoholic patients. However, mechanism of alcoholic pancreatitis remains obscure due to lack of a suitable animal model. Earlier, we reported pancreatic injury and substantial increases in endogenous formation of fatty acid ethyl esters (FAEEs) in the pancreas of hepatic alcohol dehydrogenase (ADH)-deficient (ADH(-)) deer mice fed 4% ethanol. To understand the mechanism of alcoholic pancreatitis, we evaluated dose-dependent metabolism of ethanol and related pancreatic injury in ADH(-) and hepatic ADH-normal (ADH(+)) deer mice fed 1%, 2% or 3.5% ethanol via Lieber-DeCarli liquid diet daily for 2months. Blood alcohol concentration (BAC) was remarkably increased and the concentration was ∼1.5-fold greater in ADH(-) vs. ADH(+) deer mice fed 3.5% ethanol. At the end of the experiment, remarkable increases in pancreatic FAEEs and significant pancreatic injury indicated by the presence of prominent perinuclear space, pyknotic nuclei, apoptotic bodies and dilation of glandular ER were found only in ADH(-) deer mice fed 3.5% ethanol. This pancreatic injury was further supported by increased plasma lipase and pancreatic cathepsin B (a lysosomal hydrolase capable of activating trypsinogen), trypsinogen activation peptide (by-product of trypsinogen activation process) and glucose-regulated protein 78 (endoplasmic reticulum stress marker). These findings suggest that ADH-deficiency and high alcohol levels in the body are the key factors in ethanol-induced pancreatic injury. Therefore, determining how this early stage of pancreatic injury advances to inflammation stage could be important for understanding the mechanism(s) of alcoholic pancreatitis.

Exocrine pancreatic function during the early recovery phase of acute pancreatitis.

BACKGROUND: Exocrine pancreatic dysfunction has been reported in humans in the convalescent period after acute pancreatitis, but the data are scarce and conflicting. This study aimed to prospectively assess the exocrine pancreatic function in patients with acute pancreatitis at the time of their refeeding. METHODS: Fecal elastase-1 was determined on the day of refeeding in all consecutive acute pancreatitis patients with their first episode of the disease. They were 75 patients including 60 (80.0%) patients with mild acute pancreatitis and 15 (20.0%) patients with severe acute pancreatitis. Etiologically 61 patients (81.3%) had biliary disease, 1 (1.3%) had alcoholic disease and 3 (4.0%) had hypertriglyceridemia. No causes of acute pancreatitis were found in the remaining 10 patients (13.3%). The mean (+/-SD) refeeding time after the attack of acute pancreatitis was 11.2+/-10.2 days. RESULTS: Pathological values of fecal elastase-1 were found in 9 of the 75 patients (12.0%): 7 (9.3%) patients with mild pancreatitis and 2 (2.7%) patients with severe pancreatitis (P=1.000). The frequency of the pathological values of fecal elastase-1 was significantly different from that of various etiologies of the disease (P=0.030). It was significantly lower in patients with biliary pancreatitis (9.8%; P=0.035) than in one patient with alcoholic pancreatitis (P=0.126), one patient with hypertriglyceridemia-induced pancreatitis (33.3%; P=0.708), and one patient with idiopathic pancreatitis (10.0%; P=0.227). Pathological fecal elastase-1 was not significantly related to sex, age or day of refeeding. CONCLUSION: Exocrine pancreatic function should be routinely assessed in patients with acute pancreatitis at the time of refeeding in order to supplement their diet with pancreatic extracts.

Pancreatic panniculitis: A rare form of panniculitis.

Pancreatic panniculitis is rare form of panniculitis with associated pancreatic disease. The skin manifestations can occur at any time of the pancreatic pathology. Here we report a case of pancreatic panniculitis associated with underlying chronic pancreatitis. The patient presented with painful subcutaneous nodules and the histology revealed the characteristic features of pancreatic panniculitis.

The role of epoxide hydrolase Y113H gene variant in pancreatic diseases.

OBJECTIVES: Chronic pancreatitis (CP) and pancreatic adenocarcinoma (pCA) are associated with risk factors such as alcohol intake and tobacco smoking. Microsomal epoxide hydrolase (EPHX1) is a phase II detoxifying enzyme capable of tobacco-borne toxicant inactivation. We studied the role of the EPHX1 c.337T>C (p.Y113H) variant, whichleads to altered enzyme activity, in pancreatic diseases. METHODS: We genotyped 2391 patients by melting curve analysis. We enrolled 367 patients with pCA, 341 patients with alcoholic CP (aCP), 431 patients with idiopathic CP or hereditary pancreatitis, 192 patients with acute pancreatitis, and 679 controls of German descent. We replicated data in 77 patients with aCP and 304 controls from The Netherlands. RESULTS: In German patients with aCP, Y113 was more common than in controls (allele frequencies, 0.73 vs 0.68; risk ratio, 1.21 [95% confidence interval, 1.05-1.39]). However, we could not confirm this association in the Dutch population (allele frequencies, 0.62 vs 0.68, P=not significant). In total, Y113 frequency was 0.71 in aCP and 0.68 in controls (P = not significant). Allele frequencies did not differ in the other disease groups (acute pancreatitis, 0.69; idiopathic CP or hereditary pancreatitis, 0.68; pCA, 0.68; and control, 0.68). CONCLUSIONS: The EPHX1 Y113H variant is not associated with pancreatic diseases indicating that EPHX1 does not play a significant role in the initiation of pancreatic inflammation or cancer.

Validation of fecal elastase-1 determination using immunoenzymatic assay in HIV-infected patients.

Pancreatic elastase-1 is a proteolytic enzyme exclusively produced in the pancreas, is stable when passing through the bowel, and its determination is associated with chronic pancreatitis. The clinical diagnosis of pancreatitis is based on anamnesis, physical examination, radiological, sonographic, endoscopic, and laboratory findings. Nowadays, there is a test for the determination of fecal elastase-1, by enzymatic reaction (enzyme-linked immunosorbent assay, ELISA), which specifically determines human elastase-1, promoting the pancreatic function evaluation. Parameters such as linearity, calibration curve, sensitivity, specificity, precision, accuracy, recovery, and receiver operator characteristic (ROC) curve are used to evaluate the test. The aim of this study was the validation of the immunoenzymatic assay (ELISA) and the use of its results in patients with HIV, alcoholics, and under antiretroviral therapy. The study involved 157 patients, 95 of them were HIV-infected, and 62 were completely healthy. The elastase-1 ELISA kit from Bioserv was used, and we noted that the obtained results were linear, sensitive, precise, and accurate. Moreover, our results suggest that this test can be a laboratory evaluation to determine the relationship of pancreatitis with alcohol use, but not its association with antiretroviral use in HIV patients (P=0.424). This test is useful to diagnose pathologies related to pancreatic insufficiency.

Potential for differential diagnosis of autoimmune pancreatitis and pancreatic cancer using carbonic anhydrase II antibody.

OBJECTIVES: Pancreatic ductal epithelia contain an abundance of carbonic anhydrase (CA), and the presence of antibodies to this enzyme has been described in autoimmune disorders. We previously found a small amount of an immunoglobulin G-like material in purchased CAII reagents, which led to pseudopositive reactions. METHODS: We determined the optimum measurement conditions for detecting anti-CAII antibody using an enzyme-linked immunosorbent assay and sera from 140 patients with pancreatic diseases. RESULTS: Compared with the prevalence of anti-CAII antibody in healthy subjects, a significantly higher seroprevalence of the antibody was detected in patients with autoimmune pancreatitis (AIP) (88.9%, P < 0.02), Sjögren syndrome (67.6%, P < 0.01), and alcoholic chronic pancreatitis (45.8%, P < 0.01). No positive results were obtained among patients with pancreatic cancer. Moreover, the antibody value obtained in the pancreatic cancer patients was actually lower than that obtained in healthy subjects. CONCLUSIONS: The anti-CAII antibody is probably not a specific marker of AIP because it was present at a higher frequency in the sera of patients with other pancreatic diseases. Nevertheless, the anti-CAII antibody may be a useful tool for the differential diagnosis of AIP and pancreatic cancer.

[Lipase/amylase ratio in biliary acute pancreatitis and alcoholic acute/acutized chronic pancreatitis]. / Relação lipase/amilase nas pancreatites agudas de causa biliar e nas pancreatites agudas/crônicas agudizadas de causa alcoólica.

BACKGROUND: Alcoholic or biliary acute pancreatitis may need different therapeutic approaches. AIM: Assessing the validity of lipase/amylase ratio in differentiating biliary from alcoholic acute pancreatitis/acutized chronic pancreatitis. METHODS: Nine male patients (mean age and standard deviation: 39.8 +/- 7.0 years) with alcoholic acute pancreatitis/acutized chronic pancreatitis (group I) and 29 patients, 8 male and 21 female (mean age: 43.6 +/-19.9 years), with biliary acute pancreatitis (group II) were evaluated. Serum lipase and amylase levels were measured in patients with symptoms for no more than 48 hours. The lipase/amylase ratio was calculated based on serum lipase and amylase levels and expressed as multiples of their respective superior reference values. RESULTS: Mean levels of serum lipase (4,814 +/- 3,670 U/L) and amylase (1,282 +/- 777 U/L) in patients of group I were comparable to group II (2,697 +/- 2,391 and 1,878 +/- 1,319 U/L, respectively), but the mean lipase/amylase ratio was significantly higher in group I (4.4 +/- 3.6) than in group II (2.2 +/- 2.2). Lipase/amylase ratio >3 occurred at significantly higher proportions in patients of group I (66.7%) than of group II (24.1%), differentiating the two groups with sensitivity of 67% and specificity of 76%. CONCLUSIONS: 1) Amylase and lipase serum levels did not differ in the two groups evaluated; 2) the lipase/amylase ratio >3 was more often seen in alcoholic acute pancreatitis/acutized chronic pancreatitis than biliary acute pancreatitis, and it may be useful in differentiating these two causes of pancreatitis.

Disialotransferrin, determined by capillary electrophoresis, is an accurate biomarker for alcoholic cause of acute pancreatitis.

OBJECTIVES: Serum disialotransferrin is a specific marker of heavy alcohol consumption. We tested its accuracy and probability in detecting alcoholic cause of acute pancreatitis (AP). METHODS: Blood samples from 271 consecutive AP patients, admitted to the Helsinki University Central Hospital emergency unit, were analyzed. RESULTS: The median (range) disialotransferrin value was significantly higher (P = 0.001) in AP patients with alcoholic (n = 172) 1.6% (0.3%-14.4) than with biliary (n = 60) 0.7% (0.3%-1.3%) or other causes (n = 39) 0.8% (0.3%-4.1%). In receiver operating curve analysis, disialotransferrin, as a single analyte, was significantly (P = 0.001-0.0001) more accurate (area under the curve [AUC], 0.88; 95% confidence interval [CI], 0.84-0.92) in detecting alcoholic AP as compared with glutamyl transferase (AUC, 0.51; 95% CI, 0.45-0.57), aspartate aminotransferase (AUC, 0.57; 95% CI, 0.51-0.63), alanine aminotransferase (AUC, 0.63; 95% CI, 0.57-0.69), erythrocyte mean cell volume (AUC, 0.72; 95% CI, 0.67-0.78), amylase (AUC, 0.74; 95% CI, 0.67-0.78), C-reactive protein (AUC, 0.65; 95% CI, 0.59-0.71), and bilirubin (AUC, 0.55; 95% CI, 0.49-0.62). At a disialotransferrin cutoff of 1.2%, giving an 8% false-positive rate, the positive likelihood ratio was 8.47. Thus, a positive disialotransferrin test result, performed within 24 hours of admission, increased the probability of alcoholic AP from pretest 64% to posttest 94%. CONCLUSIONS: Disialotransferrin, determined by capillary electrophoresis, is accurate, simple, and a rapid single biomarker of the alcoholic cause of AP.

Relação lipase/amilase nas pancreatites agudas de causa biliar e nas pancreatites agudas/crônicas agudizadas de causa alcoólica / Lipase/amylase ratio in biliary acute pancreatitis and alcoholic acute/acutized chronic pancreatitis

RACIONAL: Pancreatites agudas de causas alcoólica ou biliar podem necessitar de abordagens terapêuticas diferentes. OBJETIVO: Verificar a validade da relação lipase/amilase em diferenciar as causas alcoólica ou biliar na pancreatite aguda/pancreatite crônica agudizada. MÉTODOS: Foram avaliados nove pacientes com pancreatite aguda/pancreatite crônica agudizada alcoólica, todos homens, com idade média (desvio padrão) de 39,8 ± 7,0 anos (grupo I) e 29 com pancreatite aguda biliar, sendo 8 homens e 21 mulheres, com idade média de 43,6 ± 19,9 anos (grupo II). As amilasemias e lipasemias foram determinadas em pacientes com sintomatologia há, no máximo, 48 horas. A relação lipase/amilase foi calculada utilizando-se valores de amilasemia e lipasemia expressas como múltiplos de seus respectivos valores superiores de referência. RESULTADOS: As médias das lipasemias (4.814 ± 3.670 U/L) e amilasemias (1.282 ± 777 U/L) no grupo I foram semelhantes às do grupo II (2.697 ± 2.391 e 1.878 ± 1.319 U/L, respectivamente), mas a média das relações lipase/amilase foi significantemente maior no grupo I (4,4 ± 3,6) do que no grupo II (2,2 ± 2,2). Relação lipase/amilase >3 foi significantemente mais freqüente no grupo I (66,7 por cento) do que no grupo II (24,1 por cento) e diferenciou os dois grupos com sensibilidade de 67 por cento e especificidade de 76 por cento. CONCLUSÕES: 1) as amilasemias e lipasemias não diferenciaram os dois grupos avaliados; 2) relação lipase/amilase >3 é mais freqüente na pancreatite aguda/pancreatite crônica agudizada alcoólica do que na pancreatite aguda biliar, e pode ser útil na diferenciação destas duas causas de pancreatite.

BACKGROUND: Alcoholic or biliary acute pancreatitis may need different therapeutic approaches. AIM: Assessing the validity of lipase/amylase ratio in differentiating biliary from alcoholic acute pancreatitis/acutized chronic pancreatitis. METHODS: Nine male patients (mean age and standard deviation: 39.8 ± 7.0 years) with alcoholic acute pancreatitis/acutized chronic pancreatitis (group I) and 29 patients, 8 male and 21 female (mean age: 43.6 ± 19.9 years), with biliary acute pancreatitis (group II) were evaluated. Serum lipase and amylase levels were measured in patients with symptoms for no more than 48 hours. The lipase/amylase ratio was calculated based on serum lipase and amylase levels and expressed as multiples of their respective superior reference values. RESULTS: Mean levels of serum lipase (4,814 ± 3,670 U/L) and amylase (1,282 ± 777 U/L) in patients of group I were comparable to group II (2,697 ± 2,391 and 1,878 ± 1,319 U/L, respectively), but the mean lipase/amylase ratio was significantly higher in group I (4.4 ± 3.6) than in group II (2.2 ± 2.2). Lipase/amylase ratio >3 occurred at significantly higher proportions in patients of group I (66.7 percent) than of group II (24.1 percent), differentiating the two groups with sensitivity of 67 percent and specificity of 76 percent. CONCLUSIONS: 1) Amylase and lipase serum levels did not differ in the two groups evaluated; 2) the lipase/amylase ratio >3 was more often seen in alcoholic acute pancreatitis/acutized chronic pancreatitis than biliary acute pancreatitis, and it may be useful in differentiating these two causes of pancreatitis.

Alcohol/cholecystokinin-evoked pancreatic acinar basolateral exocytosis is mediated by protein kinase C alpha phosphorylation of Munc18c.

The pancreatic acinus is the functional unit of the exocrine pancreas whose role is to secrete zymogens into the gut lumen for food digestion via apical exocytosis. We previously reported that supramaximal CCK induced apical blockade and redirected exocytosis to ectopic sites on the basolateral plasma membrane (BPM) of this polarized cell, leading to pancreatitis. Basolateral exocytosis was mediated by protein kinase C phosphorylation of BPM Munc18c, causing its displacement into the cytosol and activation of BPM-bound Syntaxin-4 to form a SNARE complex. To mimic the conditions of alcoholic pancreatitis, we now examined whether 20 mm alcohol followed by submaximal CCK might mimic supramaximal CCK in inducing these pathologic exocytotic events. We show that a non-secretory but clinically relevant alcohol concentration (20 mm) inhibited submaximal CCK (50 pM)-stimulated amylase secretion by blocking apical exocytosis and redirecting exocytosis to less efficient BPM, indeed mimicking supramaximal CCK (10 nM) stimulation. We further demonstrate that basolateral exocytosis caused by both stimulation protocols is mediated by PKC alpha-induced phosphorylation of Munc18c: 1) PKC alpha is activated, which binds and induces phosphorylation of PM-Munc18c at a Thr site, and these events can be inhibited by PKC alpha blockade; 2) PKC alpha inhibition blocks Munc18c displacement from the BPM; 3) PKC alpha inhibition prevents basolateral exocytosis but does not rescue apical exocytosis. We conclude that 20 mm alcohol/submaximal CCK as well supramaximal CCK stimulation can trigger pathologic basolateral exocytosis in pancreatic acinar cells via PKC alpha-mediated activation of Munc18c, which enables Syntaxin-4 to become receptive in forming a SNARE complex in the BPM; and we further postulate this to be an underlying mechanism contributing to alcoholic pancreatitis.

[Arginase activity in blood serum of patients with acute and chronic pancreatitis]. / Aktywnosc arginazy w surowicy chorych na ostre i przewlekle zapalenie trzustki.

UNLABELLED: Pancreatitis is the most common disease of the pancreas. Difficulties in early recognition of pancreatitic diseases, particularly chronic pancreatitis, are the reason of the search for new diagnostic methods. In our earlier studies we have shown that the determination of arginase activity in serum of patients with pancreatic cancer may be useful test in preoperative diagnosis of this cancer. The aim of this study was to asses the arginase activity in serum of patients with acute and chronic pancreatitis before and after medical treatment. MATERIAL AND METHODS: Arginase activity was studied in serum of 10 patients with acute and 10 patients with chronic pancreatitis obtained before, after and/or during the medical treatment. RESULTS: The increase of arginase activity was observed in both studied groups before the medical treatment, and a statistically significant decrease after the treatment (p < 0,05). There were not significant differences between arginase activity in acute and chronic pancreatitis. CONCLUSION: Arginase activity determination seems to be useful in monitoring the treatment of patients with acute and chronic pancreatitis.

Is it long-term continuous drinking or the post-drinking withdrawal period that triggers the first acute alcoholic pancreatitis?

OBJECTIVE: Unlike patients with alcoholic hepatitis, patients with acute alcoholic pancreatitis seldom come into the hospital in an intoxicated state. Long-term history of heavy drinking induces increases in the serum pancreatic enzymes and pancreatitis-associated protein profiles during the withdrawal period. The aim of this study was to investigate the role of withdrawal in triggering acute alcoholic pancreatitis by studying the time-course of development of the first symptoms of the first acute alcoholic pancreatitis. MATERIAL AND METHODS: One hundred patients (85 M, 15 F, mean age 46, range 18-73 years) with the first acute alcoholic pancreatitis were asked three different questions in an attempt to clarify the same issue: Had you already stopped continuous drinking before the start of the acute abdominal pain that later led to hospitalization? Had you already stopped continuous drinking before you started to experience nausea or vomiting? How many hours after taking the last drop of alcohol did you start to feel pain (0 h, 1<6 h, 7-12 h, 13-24 h, 25-48 h, >48 h)? The amount of alcohol consumed was evaluated 1) during the past week and 2) during the past 2 months. The severity of the pancreatitis was assessed by serum C-reactive protein concentration, presence of necrosis, the development of pancreatic complications and the length of stay in hospital and in the intensive care unit. RESULTS: Eighty-five patients were able to respond to the questions. Of these, 69% had developed pain and 91% nausea/vomiting only after they had already stopped continuous drinking. Whereas 29% of the patients developed some symptoms before stopping drinking, the majority of the patients developed symptoms during the first day after cessation (43%) or later (28%), mainly during the second day of cessation of drinking. In both the univariate analysis and the multivariate analysis the timing of the symptoms was dependent on the amount of alcohol consumed during the previous 2 months and in the past week. CONCLUSIONS: In the majority of patients with first acute alcoholic pancreatitis, the symptoms begin during the early withdrawal period. The withdrawal period might be more important than previously emphasized in the development of acute alcoholic pancreatitis.

Predictive factors for pseudocysts and peripancreatic collections in acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is a proteiform disease which may lead to various complications. Pancreatic pseudocysts and fluid collections are among the most frequent of them. The aim of our study was to find predictive factors of their occurrence. METHODS: We carried out a retrospective cohort study comprising one year patients admitted to our department with AP. Fisher's exact and U Mann Whitney tests were used for correlations, with a probability of error < 5% (p<0.05). RESULTS: We included 62 patients with a mean age of 49 years; 77.4% were males. AP etiology was due to alcohol (58.1%), biliary disorders (22.6%), hyper-triglycerides (8.1%) and post-ERCP (3.2%). Pancreatic cancer was revealed in (6.5%) patients. From the whole group 2 patients (3.2%) died. There were 22 patients with pseudocysts (35.5%) and 13 patients with acute fluid collections (21%). Multiple pseudocysts were present in 12 cases (54.5%), mean diameter was 39.5 mm. Pancreatic head localization was most frequent (63.6%). Alcoholic etiology was associated with acute pseudocysts formation (p=0.007) as well as lower values of alkaline phosphatase (96 U/L versus 286 U/L, p = 0.016). The area under the receiver operating characteristics curve demonstrated values of alkaline phosphatase < 2 x upper normal values were predicting pseudocyst occurrence with > 90% specificity. Presence of ascites predicted formation of acute fluid collections, (p < 0.001). CONCLUSIONS: Alcoholic etiology and low values of serum alkaline phosphatase seem to predict pseudocysts formation in acute pancreatitis, while ascites forecast acute fluid collections occurrence.