Cholecystokinin in acute alcoholic and biliary pancreatitis.

BACKGROUND: Recent studies have shown that cholecystokinin (CCK) agonist, cerulein can induce acute pancreatitis in animals. The role of CCK in the induction of acute pancreatitis in humans is unclear. We investigated plasma CCK levels in alcoholic and biliary pancreatitis on admission and during the episode of acute pancreatitis. METHODS: Plasma CCK concentrations were determined by a specific and sensitive radioimmunoassay using CCK antiserum (Euro-Diagnostica, Malm?, Sweden) in 35 patients with acute alcoholic pancreatitis, in 27 patients with acute biliary pancreatitis, in 34 patients with nonpancreatic acute abdominal pain, and in 43 healthy subjects. The mean time from the first symptoms to the plasma sample was 31 (+/- 3.7) h in alcoholic pancreatitis patients and 25 (+/- 5.1) h in biliary pancreatitis patients. We also determined CCK levels in 20 patients during the episode of acute pancreatitis. Normal fasting level of CCK is < or = 1.12 pmol/L according to manufacturer. RESULTS: Basal plasma CCK concentrations were significantly lower both in alcoholic pancreatitis (mean +/- SEM, 0.04 +/- 0.03 pmol/L, p < 0.0001) and biliary pancreatitis patients (0.17 +/- 0.13 pmol/L, p < 0.0001) than in nonpancreatic acute abdominal pain patients (1.23 +/- 0.32 pmol/L) or healthy subjects (1.18 +/- 0.20 pmol/L). Plasma CCK levels also remained low until the patient was well-recovering and had started oral diet. CONCLUSION: Basal plasma CCK concentrations are significantly decreased in acute alcoholic and biliary pancreatitis after the first day from the beginning of the symptoms until the patient was well-recovering.     

Progression of alcoholic acute to chronic pancreatitis.

Alcoholic chronic pancreatitis usually progresses from acute attacks to chronic pancreatitis within one to 19 years. The factors responsible for the appreciable variability in progression are unclear. In this study the relation between progression and the incidence and severity of acute episodes in a large cohort of patients with alcoholic chronic pancreatitis was analysed. All patients with at least one documented episode of acute pancreatitis have been studied prospectively over the past 30 years according to our protocol. Patients were classified according to their long term course into (a) calcific (n = 185), (b) non-calcific (n = 30), and (c) non-progressive (n = 39) chronic pancreatitis groups. The yearly incidence of acute attacks of pancreatitis was significantly higher in groups (a) and (b) than in group (c). Furthermore, the progression rate to advanced chronic pancreatitis (groups (a) and (b)) correlated with the incidence of severe pancreatitis (associated with pseudocysts in more than 55%). Pseudocysts were located primarily in the cephalic pancreas in groups (a) and (b) (58-71%) and in the pancreatic tail in group (c) (61%). In conclusion, these data suggest that the progression of acute to chronic pancreatitis is closely related to the incidence and severity of acute attacks. This finding and the primary location of pseudocysts in the cephalic pancreas (groups (a) plus (b)) are compatible with the ''necrosis-fibrosis'' pathogenetic hypothesis.     

Treatment of acute alcoholic pancreatitis in cats

We created acute pancreatitis in cats by instilling ethanol (20 ml of a 40% solution) into the stomach and then perfusing activated pancreatic enzymes through the main pancreatic duct. Edematous pancreatitis developed within 24 h as the enzymes leaked out of the duct into the surrounding pancreatic parenchyma. We tested the effects of a number of agents on the amelioration of the severity of the pancreatic inflammation. Cimetidine (an H2 receptor blocker) and Benadryl (an H1 receptor blocker) given in combination decreased the incidence of pancreatic hemorrhage but not the overall degree of inflammation. Indomethacin (a cyclooxygenase inhibitor) had a similar effect. Terbutaline (a beta-agonist) given alone decreased the overall degree of inflammation, including the incidence of hemorrhage. All of the drugs given together were no more effective than terbutaline alone. The combination was effective even when given up to 12 h after the onset of pancreatitis.     

Cholecystokinin in acute alcoholic and biliary pancreatitis

Summary Background. Recent studies have shown that cholecystokinin (CCK) agonist, cerulein can induce acute pancreatitis in animals. The role of CCK in the induction of acute pancreatitis in humans is unclear. We investigated plasma CCK levels in alcoholic and biliary pancreatitis on admission and during the episode of acute pancreatitis. Methods. Plasma CCK concentrations were determined by a specific and sensitive radioimmunoassay using CCK antiserum (Euro-Diagnostica, Malm?, Sweden) in 35 patients with acute alcoholic pancreatitis, in 27 patients with acute biliary pancreatitis, in 34 patients with nonpancreatic acute abdominal pain, and in 43 healthy subjects. The mean time from the first symptoms to the plasma sample was 31 (±3.7) h in alcoholic pancreatitis patients and 25 (±5.1) h in biliary pancreatitis patients. We also determined CCK levels in 20 patients during the episode of acute pancreatitis. Normal fasting level of CCK is ≤1.12 pmol/L according to manufacturer. Results. Basal plasma CCK concentrations were significantly lower both in alcoholic pancreatitis (mean ± SEM, 0.04±0.03 pmol/L, p<0.0001) and biliary pancreatitis patients (0.17±0.13 pmol/L, p<0.0001) than in nonpancreatic acute abdominal pain patients (1.23±0.32 pmol/L) or healthy subjects (1.18±0.20 pmol/L). Plasma CCK levels also remained low until the patient was well-recovering and had started oral diet. Conclusion. Basal plasma CCK concentrations are significantly decreased in acute alcoholic and biliary pancreatitis after the first day from the beginning of the symptoms until the patient was well-recovering.     

酒精性重症急性胰腺炎的临床特征

目的 探讨酒精性重症急性胰腺炎(SAP)的临床特征.方法 回顾性分析2001年1月至2008年12月福建省立医院收治的重症急性胰腺炎(SAP)患者166例.根据发病前12～48h内有无大量饮酒分成酒精性SAP组(43例)和非酒精性SAP组(123例),分析两组年龄,性别,入院时CT评分、APACHEⅡ评分、血糖、血清三酰甘油、血钙、血清白蛋白、并发症及后期感染率、病死率的差异.结果 两组年龄无统计学差异,酒精性SAP组男性的构成比(39/43)明显高于非酒精性SAP组(58/123,P＜0.01).入院时两组CT评分、血糖及血钙无统计学差异.酒精性SAP组APACHEⅡ评分为19.16±5.38,血清三酰甘油水平为(5.06±4.03)mmol/L,均显著高于非酒精性SAP组的16.02±5.09和(3.12±2.95)mmol/L(P＜0.05),而血清白蛋白(25.23±7.12)g/L则明显低于非酒精性SAP组的(30.68±8.35)g/L(P＜0.01).酒精性SAP组急性呼吸窘迫综合征、上消化道出血发生率与非酒精性SAP组无统计学差异,但急性肾功能衰竭(44.2%)、肝功能衰竭(41.9%)、心功能衰竭(37.2%)、休克(39.5%)、感染的发生率(27.9%)及病死率(30.2%)明显高于非酒精性SAP组(分别为26.0%、30.9%、20.3%、16.3%、16.3%、7.3%,P＜0.05或＜0.01).结论 酒精性SAP患者以男性为主,并发症多,病死率高.改变酗酒的不良嗜好是预防酒精性SAP的有效措施.     

Pathobiology of alcoholic pancreatitis.

This paper provides a summary of the effects of alcohol abuse on the pathobiologic responses that occur during acute and chronic pancreatitis considering both the human disease and animal/tissue models. The effects are multiple and include ones on cell death leading to necrosis; on inflammation resulting in a sensitized response to pancreatic stress; and fibrosis through effects of ethanol on pancreatic stellate cells and the plasminogen system. Although the effects of alcohol are multiple and complex, it is likely that a combination of a few key effects on these pathobiologic responses drive the increased sensitivity of the pancreas to acute pancreatitis with pancreatic stress and the promotion of chronic pancreatitis with pancreatic injury occurring during acute pancreatitis.     

Lipase/amylase ratio in biliary acute pancreatitis and alcoholic acute/acutized chronic pancreatitis

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.     

A search for acute necrotic pancreatitis in early stages of alcoholic chronic pancreatitis

OBJECTIVES: Various investigators believe that alcoholic chronic pancreatitis is the result of recurrent episodes of acute necrotic pancreatitis. The aim of this work is to study pancreatic histology in early stages of the disease to search for evidence of these acute episodes. STUDY: Of about 650 patients with alcoholic pancreatitis seen during the 30-year period from 1972 to 2002, 45 underwent surgery for this disease, all within 2 years of clinical onset. Of these 45, tissue samples adequate for study were obtained from 42, and this was the study material. Tissue samples were prepared for histologic examination by standard procedures. RESULTS: Areas of pancreatic necrosis were seen in tissue samples of only three (7%) of the 42 patients, and in all three cases chronic lesions were also present. No evidence of localized scarring that could be attributed to prior episodes of focal necrotic pancreatitis was found. A typical feature was the patchy distribution of the lesions in largely normal pancreatic tissue. The main lesions observed were perilobular and intralobular fibrosis, dilation of acini and ducts, and protein plugs in dilated ducts surrounded by periductal fibrosis. CONCLUSIONS: This study shows that, in the early stages of alcoholic chronic pancreatitis, signs of acute necrotic pancreatitis are very infrequent and, when present, they are associated with chronic lesions. These findings suggest that alcoholic pancreatitis begins as a chronic disease.     

暴发性急性胰腺炎动物模型的建立

目的建立暴发性急性胰腺炎模型,为研究其发病机制提供实验模型。方法30只SD大鼠随机分为假手术组、ANP组、LPS加重组、LPS BPDL(胆胰管结扎)组和LPS GdCl3组,各6只。于制模术后6h观察各组最大采血量、腹水量及血清谷丙转氨酶、肌酐、淀粉酶、TNF-α的含量和腹水淀粉酶、TNF-α的含量,并对胰腺、肺脏、肝脏和肾脏做病理检查。结果LPS加重组、LPS BPDL组的腹水量、谷丙转氨酶、肌酐、淀粉酶、TNF-α均较ANP组、假手术组明显升高;而最大采血量明显减少;肺脏和肝脏病理分值显著升高(均P<0.05或0.01)。LPS BPDL组较LPS加重组的病情严重程度更重。LPS GdCl3组较LPS加重组的有效循环血量和肝肾功能明显改善,肺脏组织病理学改变明显减轻。结论在ANP基础上从胆胰管内加注内毒素可产生较ANP更为严重的病理损伤,可以作为一种暴发性急性胰腺炎的模型。     

Theories, mechanisms, and models of alcoholic chronic pancreatitis

Alcoholic chronic pancreatitis is a severe, disabling, chronic inflammatory condition of the pancreas that is seen in fewer than 5% of alcoholics. The severity and unpredictability of this condition has lead to several theories on the mechanism causing chronic pancreatitis based on careful clinical observation. Hypothetical mechanisms were applied to various animal models. Finally, following multiple lines of evidence, there is a convergence of thought and development of some new models that are quite instructive. Taken together, chronic alcohol consumption by rats results in multiple effects on the pancreas that increase the risk of acute pancreatitis, including ongoing acinar cell injury that lowers the threshold for hyperstimulation-induced acute pancreatitis, neurohormonal injury, and adaptation that results in acinar cell hyperstimulation, increased susceptibility to viral mediated acute pancreatitis, and possibly other factors. After acute pancreatitis initiates the inflammatory process, the chronic inflammation and fibrosis of alcoholic chronic pancreatitis are driven by diet, the acinar cell stress response to continued alcohol that may be potentiated by toxic alcohol metabolites, hypoxia, hyperstimulation, and partial duct obstruction; plus the effects of proinflammatory immunocytes and cytokines; and by stellate cell-mediated fibrosis driven by anti-inflammatory cytokines, alcohol, and alcohol metabolites. The factors determining which alcoholic will develop alcoholic chronic pancreatitis likely involve genetic factors, dietary factors, and susceptibility to pancreatic injury through several mechanisms ranging from trauma to gallstones to viruses.     

Serum lipase: a better test to diagnose acute alcoholic pancreatitis.

OBJECTIVE: To determine whether serum lipase is a better test than serum amylase to diagnose acute alcoholic pancreatitis. PATIENTS: Two hundred two asymptomatic chronic alcoholics (Group A) and 29 patients with image-proven pancreatitis (Group P). MEASUREMENTS: Serum lipase was measured using the Kodak Ektachem clinical chemistry slide. Serum amylase was estimated using the Kodak Ektachem clinical chemistry slide or the Beckman Astra amylase chemistry module. RESULTS: The level of serum amylase in Group A ranged from 17 to 347 U/L (mean 71, SD +/- 36 U/L) and in Group P from 180 to 2,985 U/L (mean 722, SD +/- 663 U/L). Thirteen of 29 patients (45%) with image-proven pancreatitis had levels that overlapped those found in asymptomatic alcoholics. The serum lipase levels in Group A ranged from 34 to 600 U/L (mean 186, SD +/- 111 U/L), while in Group P, the corresponding figures were 1,011 to 25,706 U/L (mean 5,822, SD +/- 5,664 U/L). None of the 29 patients with image-proven pancreatitis had levels that overlapped those found in asymptomatic alcoholics. CONCLUSIONS: Serum lipase is a better test that serum amylase to diagnose acute alcoholic pancreatitis.     

Cholinergic hypothesis of alcoholic pancreatitis.

Chronic alcohol intake interferes especially with the two main pathways regulating exocrine pancreatic secretion: the cholinergic and the pancreozymin pathway. Recently, a new theory of the pathogenesis of alcoholic pancreatitis was proposed emphasizing disordered agonist-receptor interaction at the level of pancreatic acinar cells. Accordingly, alcohol-induced alterations in the control of exocrine pancreatic secretion result in hyperstimulation of pancreatic acinar cells and their muscarinic receptors, mimicking the mechanism of acute pancreatitis caused by scorpion sting, intoxication with an anti-acetylcholinesterase-containing insecticide or supramaximal doses of secretagogues. The present review emphasizes the role of these alcohol-induced secretory alterations in the pathogenesis of alcoholic pancreatitis.     

Influence of bouts of acute pancreatitis on the course of chronic alcoholic pancreatitis in man

The purpose of this study was to ascertain the influence of acute pancreatitis upon the course of chronic pancreatitis, its complications, the need for surgical treatment, and mortality, in alcoholic men. The studied population was composed of 222 men; 110 had never had acute pancreatitis and 112 had presented at least once with acute pancreatitis. The cumulative probability to have a first bout of acute pancreatitis was 41.5 percent, 2 years after the onset of chronic pancreatitis. There was no difference in follow-up but clinical onset of chronic pancreatitis was earlier in the "acute pancreatitis" group. There was no difference in the prevalence of biliary strictures, non-alcoholic hepatic disease or need for surgery. On the contrary, diabetes mellitus, alcoholic hepatic disease were less frequent and pseudocysts were more frequent in the "acute pancreatitis" group. We observed 56 deaths. The comparison of mortality and cumulative survival rates showed a lower mortality in the "acute pancreatitis" group (p less than 0.02 and 0.05, respectively). The main causes of death were alcohol-related hepatic disease, postoperative mortality, and carcinoma Alcoholic cirrhosis was more frequent in patients who died in the "no acute pancreatitis" group. We conclude that: a) acute pancreatitis is an early complication of chronic pancreatitis in one case out of two; b) clinical onset of chronic pancreatitis occurs earlier in patients who presented with acute pancreatitis; c) need for surgery is not different; d) alcoholic hepatic disease is more frequent in the "no acute pancreatitis" group; e) mortality is lower in the "acute pancreatitis" group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Animal and in vitro models of alcoholic pancreatitis: role of cholecystokinin

Although ethanol abuse is the major etiologic factor in the development of acute and chronic pancreatitis, the mechanisms of ethanol effects to cause pancreatitis are poorly understood. The major reason for the lack of progress is the relative lack of animal models that reproduce the deleterious effects of ethanol on the pancreas that are observed in human disease. We propose that the effect of ethanol on the pancreas is due to its ability to sensitize animals and humans to the potentially injurious effects of other stimuli. We have developed models of ethanol-induced acute and chronic pancreatitis in rats as well as pancreatic acinar cells in primary culture demonstrating that ethanol sensitizes the pancreas to the inflammatory, cell death, and fibrosing responses caused by cholecystokinin (CCK). Our results indicate that the ethanol-sensitized inflammatory response is the key or trigger event for the development of the other pathologic responses in both acute and chronic pancreatitis, such as cell death, intracellular digestive enzyme activation, and fibrosis. These findings suggest that experimental strategies designed to reveal the modulating effects of ethanol on the mechanisms underlying the inflammatory, cell death, and fibrosing responses stimulated by CCK will provide the key information needed to understand how ethanol abuse causes pancreatitis.     

Emerging concepts for the mechanism of alcoholic pancreatitis from experimental models

The pathophysiologic mechanisms that underlie acute and chronic pancreatitis arising from alcohol abuse are poorly understood. The reasons for this state of knowledge result historically from a lack of models for experimental investigation. Ethanol feeding alone, even at high doses, has minimal and inconsistent effects on morphologic findings in the pancreas in experimental animals. This experience, plus the fact that alcohol abuse causes pancreatic pathology in only a minority of patients, suggest that ethanol acts to sensitize the pancreas to the deleterious effects of other stimuli. In this article, we discuss findings to support this concept of ethanol as a sensitizing agent and experimental models developed that can be used to investigate the effects of ethanol on the pathologic processes of pancreatitis. These pathologic processes include inflammation, cell death, intrapancreatic digestive enzyme activation, and fibrosis.     

Lipase/amylase ratio. A new index that distinguishes acute episodes of alcoholic from nonalcoholic acute pancreatitis.

Because of observations that patients with acute episodes of alcoholic pancreatitis had high serum lipase levels whereas patients with gall stone pancreatitis had high serum amylase levels, a prospective study was undertaken to determine whether the ratio of serum lipase to serum amylase, a newly computed ratio, would discriminate between acute episodes of alcoholic and nonalcoholic pancreatitis. In phase one, 30 consecutive patients with acute pancreatitis were entered into the study and divided into groups A and B. Patients with renal failure were excluded from the study. Group A consisted of 20 patients in whom the etiology of pancreatitis was alcohol. Group B consisted of 10 patients whose pancreatitis was nonalcoholic in etiology (predominantly gallstones). Serum lipase values in group A ranged 492 to 25,706 U/L (median, 3433 U/L) and in group B from 711 to 31,153 U/L (median, 1260 U/L). These differences were not significant statistically. Serum amylase values in group A ranged from 104 to 2985 U/L (median, 331 U/L) and in group B from 423 to 13,000 (median, 1187 U/L). Although these figures were statistically different (P less than 0.005), there was a considerable degree of overlap in the values between the two groups. The lipase/amylase ratio calculated from the blood sample obtained at presentation appeared to be a promising discriminatory index. The lipase/amylase ratio was calculated by using the amylase and lipase levels expressed as multiples of the upper limit of normal in each case. The lipase/amylase ratios in the alcoholic group ranged from 2.2 to 14.8, whereas the lipase/amylase ratio in nonalcoholic pancreatitis ranged from 0.31 to 1.93. These differences were statistically significant (P less than 0.005). A lipase/amylase ratio of greater than 2 was indicative of an alcoholic etiology, and a ratio of less than 2 suggested that the pancreatitis was nonalcoholic in nature. In phase two, this lipase/amylase ratio of 2 was applied prospectively to an unselected population of 21 consecutive patients with acute pancreatitis. Thirteen patients had a lipase/amylase ratio of greater than 2; in 11 of them, the etiology of the pancreatitis was alcohol. Eight patients had a lipase/amylase ratio of less than 2; of them, only 1 patient had an alcoholic etiology for the pancreatitis. These differences were statistically significant (P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)     

Hepatic fibrogenic activity in chronic alcoholic pancreatitis.

The prevalence and the mechanisms of hepatic fibrosis in chronic alcoholic pancreatitis remain uncertain. The aim of this study was to investigate the fibrogenic activity of the liver in patients with chronic pancreatitis and its relation with either the alcohol or cholestasis. Liver biopsies were obtained from 16 patients with chronic pancreatitis at the time of surgery and from 10 organ donors. Samples were processed for histologic examination to assess the presence and extent of fibrosis, inflammatory reactions, and cholestasis- and alcohol-related lesions. In other samples, the collagen content was measured by morphometry, and prolylhydroxylase activity was determined. Liver-function tests, ultrasonography, and endoscopic retrograde cholangiopancreatography were performed before surgery in all the patients. Of patients with chronic pancreatitis, 75% had significantly greater hepatic fibrosis and prolylhydroxylase activity than the control group. Moreover, prolylhydroxylase activity in patients with chronic pancreatitis was higher in those with cholestasis or partial obstruction of the common bile duct than in those without cholestasis or partial obstruction of the common bile duct. Both the fibrogenic activity and the collagen content in the livers of patients with chronic alcoholic pancreatitis are significantly increased, even in those without histologic lesions, and these alterations may be secondary to a partial occlusion of the common bile duct.     

Prevalence of normal serum amylase levels in patients with acute alcoholic pancreatitis

Acute alcoholic pancreatitis is uncommonly diagnosed when the serum amylase level is normal. We defined acute alcoholic pancreatitis as a clinical syndrome in which hyperamylasemia was not a necessary component and sought support for the diagnosis by ultrasonography and computed tomography of the pancreas. In 68 episodes of acute alcoholic pancreatitis identified in a one-year period, the serum amylase level was normal at the time of hospital admission in 32%. In 40 episodes, we performed ultrasonography and computed tomography within 48 hr of admission. The diagnosis was supported by ultrasonography in 43%, by computed tomography in 68%. Ultrasonography and computed tomography supported the diagnosis as frequently in patients with normal serum amylase levels as in patients with hyperamylasemia. We conclude that patients with acute alcoholic pancreatitis frequently have normal serum amylase levels. The widespread clinical practice of relying solely on hyperamylasemia to establish the diagnosis of acute alcoholic pancreatitis is unjustified and should be abandoned.