Gyula Farkas

Acute pancreatitis in five European countries: etiology and mortality.

Introduction In recent years, many advances have been made in the diagnosis and treatment of acute pancreatitis that have lead to a significant reduction in both morbidity and mortality; however, knowledge of the etiology and of the relation between etiology and mortality is far from complete. Aim To obtain a more comprehensive view of the etiology and mortality of acute pancreatitis in Europe than has been given by previous single-center studies. Methodology The study comprised 1,068 patients in five European countries who were admitted to hospitals for acute pancreatitis from January 1990 to December 1994. Data for each patient were collected on a standardized form. Results Of the 1,068 patients (692 men, 376 women; mean age, 52.8 years; range, 10–95 years), 589 had edematous pancreatitis, and 479 the necrotic form. Cholelithiasis (37.1%) and alcohol (41.0%) were the most frequent etiologic factors. In Germany, cholelithiasis and alcohol occurred with similar frequency (34.9 and 37.9%, respectively); in Hungary, alcohol predominates over cholelithiasis (60.7 vs. 24.0%); in France, a small predominance of alcohol was seen (38.5 vs. 24.6%); and in Greece and Italy, there was a clear predominance of cholelithiasis over alcohol (71.4 vs. 6.0% and 60.3 vs. 13.2%, respectively). The differences in the frequency of cholelithiasis and alcohol between Greece and Italy and the other countries were statistically significant (p < 0.01). Eighty-three patients (7.8%) died of acute pancreatitis; 77 (16.1%) had necrotic disease and 6 (1.0%) edematous. There was no statistically significant difference in mortality among the etiologic groups, and no relation was found between mortality and age. Conclusion Both cholelithiasis and alcohol were main etiologic factors in the more northern countries studied, whereas cholelithiasis alone predominated in the more southern ones. Mortality was high for necrotic pancreatitis; it was similar among the various etiologic groups, and there was no relationship between mortality and age.

An update on recurrent acute pancreatitis: data from five European countries

OBJECTIVE:A great number of studies have been published on acute pancreatitis, but few have focused on the recurrent form. In this study, we have sought to determine the relative frequency and mortality of recurrent acute pancreatitis, and also to update our knowledge of its etiological factors.METHODS:Patients were selected from a total of 1068 persons included in a previous European study of acute pancreatitis. All were admitted to a hospital with an attack of acute pancreatitis between January, 1990 and December, 1994. Data for each patient was recorded on a standardized form.RESULTS:Of the 1068 with acute pancreatitis, 288 (27%) had recurrent pancreatitis; the majority (78.8%) were men, with a mean age of 43 yr (range 16–95 yr). Regarding etiology, alcohol was the most frequent factor (57%), followed by gallstones (25%), other factors (7.6%), and no identified factor (10.4%). Of the 288 patients, 17 (5.9%) died, all of whom had necrotizing pancreatitis; among all of the patients with necrotizing pancreatitis (141 of 288), the mortality was 12.1%. These percentages are lower than those for patients who had a single attack (8.5% and 18.6%, respectively), but not to a statistically significant degree. Mortality was significantly lower among patients with alcoholic pancreatitis (6.9%) than among those with biliary (30%) (p < 0.002) or idiopathic pancreatitis (25%) (p < 0.04). Most of the deaths (82.4%) occurred at the second attack of pancreatitis.CONCLUSION:Acute recurrent pancreatitis remains a frequent disease, with alcohol being the most frequent etiological factor. Mortality is similar to that of a single episode of acute pancreatitis, and it is significantly lower among patients with alcohol as the etiology.

Polymorphism of the TNF-alpha, HSP70-2, and CD14 genes increases susceptibility to severe acute pancreatitis.

Objectives: Proinflammatory cytokines and heat shock proteins play fundamental roles in the pathogenesis of acute pancreatitis. We studied whether polymorphisms of the tumor necrosis factor α (TNF-α), heat shock protein 70-2 (HSP70-2), and CD14 genes correlate with the severity of acute pancreatitis. Methods: Patients with acute pancreatitis (n = 77) of mixed etiology were grouped according to the severity of the disease on the basis of the Ranson scores. Healthy blood donors (n = 71) served as controls. TNF-α-308 polymorphism was determined by NcoI RFLP, HSP70-2 polymorphism by PstI RFLP, and CD14-159 polymorphism by melting point analysis. Results: There was a moderate increase in the frequency of the TNF1/2 genotype (P = 0.046) among patients with severe acute pancreatitis as compared with those with mild disease. A more significant increase was observed in the frequency of the HSP70-2 G allele between groups of patients with mild or severe pancreatitis (18.9% vs. 53%; P < 0.001). Conversely, the A/A genotype was markedly more frequent among the patients with mild pancreatitis (P < 0.0001). There was no significant correlation between CD14-159 promoter polymorphism and the severity of pancreatitis. Conclusion: High frequencies of the HSP70-2 G and the TNF-α -308 A alleles were associated with risk of severe acute pancreatitis. Genotype assessments may be important prognostic tools to predict disease severity and the course of acute pancreatitis. Therefore, genotype assessments may also be used to guide treatment or to identify risk populations for severe acute pancreatitis.

Surgical Management and Complex Treatment of Infected Pancreatic Necrosis: 18-Year Experience at a Single Center

Infected pancreatic necrosis (IPN), the most severe form of acute pancreatitis, is responsible for most cases of pancreatitis-related morbidity and mortality. Since 1986, 220 patients with IPN have been treated. The surgical treatment was performed on average 18.5 days (range, 8–25 days) after the onset of acute pancreatitis and consisted of wide-ranging necrosectomy, combined with widespread drainage and continuous lavage. In 108 of the 220 cases, some other surgical intervention (distal pancreatic resection, splenectomy, total pancreatectomy, cholecystectomy, colon resection, etc.) was also performed. Following surgery, the supportive therapy consisted of immunonutrition (glutamine and arginine supplementation) and modification of cytokine production with pentoxifylline and dexamethasone. Continuous lavage was applied for an average of 44.5 days (range, 21–95 days), with an average of 9.5 L (range, 5–20 L) of saline per day. The bacteriologic findings revealed mainly enteral bacteria, but Candida infection was also frequently detected (21%). Forty-eight patients (22%) had to undergo reoperation. The overall hospital mortality was 7.7% (17 patients died). In our experience, IPN responds well to adequate surgical treatment, continuous, longstanding widespread drainage and lavage, together with supportive therapy consisting of immunonutrition and modification of cytokine production, combined with adequate antibiotic and antifungal medication.

Plasma Concentrations of High-Mobility Group Box Protein 1, Soluble Receptor for Advanced Glycation End-Products and Circulating DNA in Patients with Acute Pancreatitis

Aims: High-mobility group box protein 1 (HMGB1), a late-acting proinflammatory cytokine, is secreted actively by inflammatory cells, and released passively from necrotic cells. From the aspect that both inflammation and necrosis are involved in the pathogenesis in acute pancreatitis, the aim of the study was a joint investigation of the plasma concentrations of HMGB1, its soluble receptor for advanced glycation end-products (sRAGE), and the circulating DNA as a marker of cell death. Methods: 62 patients with acute pancreatitis (30 mild, 32 severe), 20 patients with sepsis, and 20 healthy controls were enrolled in the study. HMGB1 and sRAGE plasma levels were measured by means of ELISA. Plasma DNA concentrations were estimated by real-time quantitative PCR for the β-globin gene. Results: The circulating HMGB1 level was significantly higher in patients with severe acute pancreatitis (13.33 ± 2.11 ng/ml) than in healthy controls (0.161 ± 0.03 ng/ml) or than in patients with mild pancreatitis (2.64 ± 0.185 ng/ml). The plasma concentration of sRAGE was highest in patients with sepsis (2,210 ± 252 pg/ml), while the levels of sRAGE correlated inversely with that of HMGB1 in patients with acute pancreatitis. The plasma DNA level was significantly elevated in patients with severe acute pancreatitis (2,206 ± 452 ng/ml). Conclusion: A complex study of the plasma levels of HMGB1, sRAGE and circulating DNA can be informative in evaluations of acute pancreatitis with different levels of severity.

The possible role of F-18 FDG positron emission tomography in the differential diagnosis of focal pancreatic lesions

Purpose To compare the diagnostic values of different methods for the differentiation of malignant from benign pancreatic lesions. Methods In 22 patients with focal pancreatic lesions, the carbohydrate antigen (CA) 19-9 level was measured; abdominal ultrasound (US), computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP), and F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) were performed; and the value of these methods were analyzed for their use in cancer diagnosis. Results Malignant lesions were identified in six patients and verified by surgery or clinical follow-up. The CA 19-9 level was elevated in four of the five patients examined (sensitivity, 80%). In all six cases, US and CT revealed hypoechogenic and hypodense areas (sensitivity, 100%). In one patient, ERCP was unsuccessful but yielded true-positive results in three others (sensitivity, 60%). The sensitivity of FDG PET was 100%. Sixteen focal cases of pancreatic disease proved to be benign. The CA 19-9 level was elevated in four of them (specificity, 73%). Hypoechogenic and hypodense areas were evident on US and CT in eight patients. The specificity of CT was 50% (8 of 16 cases). The specificity of US was 47% (7 of 15 cases). The specificity of successful ERCP was 92%. Fourteen negative FDG-PET results were truly negative. In two patients, however, the PET findings proved to be falsely positive (specificity, 88%). Conclusions FDG-PET is an effective tool to differentiate malignant from benign focal pancreatic lesions. In persons with focal pancreatic hypoechogenic or hypodense lesions detected by CT or US and an elevated CA 19-9 level, FDG PET should be the next step in the diagnostic strategy.

Polymorphism in the IL-8 gene, but not in the TLR4 gene, increases the severity of acute pancreatitis.

Background/Aim: Activated granulocytes and inflammatory mediators of the innate immune response play fundamental roles in the pathogenesis of acute pancreatitis. We studied whether polymorphisms of interleukin-8 (IL-8) and Toll-like receptor 4 (TLR4) genes correlate with the severity of acute pancreatitis. Methods: Patients with acute pancreatitis (n = 92) were grouped according to the severity of the disease on the basis of the Ranson scores. Healthy blood donors (n = 200) served as controls. The IL-8 –251 gene polymorphism was analyzed by amplification-refractory mutation system; the single-nucleotide polymorphisms (Asp299Gly and Thr399Ile) of TLR4 were investigated by using a real-time polymerase chain reaction method with melting point analysis. Results: The IL-8 A/T heterozygote mutant variants were detected with a significantly higher frequency among the patients with severe pancreatitis than among the healthy blood donors (60 vs. 42%; p = 0.0264, odds ratio = 2.071, 95% confidence interval = 1.101–3.896), while the frequency of the normal allelic genotype (TT) was higher among the patients with mild pancreatitis than in the group with severe pancreatitis (35 vs. 16%; p = 0.051, odds ratio = 2.917, 95% confidence interval = 1.089–7.811). There was no significant correlation between TLR4 polymorphisms and the acute pancreatitis itself, but nonsignificantly increased frequencies of Asp299Gly and Thr399Ile heterozygotes among patients with severe infected pancreatic necrosis could be observed relative to the patients with mild pancreatitis. Conclusions: Determination of the frequency of IL-8 polymorphism in acute pancreatitis may be informative and may provide further evidence concerning the role of IL-8 in the severe form of this disease. The possible role of TLR4 polymorphism in the outcome of severe acute pancreatitis requires further investigations in a larger series of patients.

Organ-preserving pancreatic head resection in chronic pancreatitis†

Twenty to thirty per cent of patients with chronic pancreatitis develop inflammatory enlargement of the head of the pancreas. A safe procedure has been developed for duodenum‐preserving pancreatic head resection; this report describes the preliminary results achieved.

Necrolytic migratory erythema

Background:  Necrolytic migratory erythema is considered to be a paraneoplastic dermatosis. The classical symptoms are associated with α‐cell pancreatic islet cell tumor or ‘glucagonoma’. Generally, extracutaneous hallmarks of this disease include weight loss, diabetes, anaemia and diarrhoea.

Time-course changes in serum cytokine levels in two experimental acute pancreatitis models in rats

Activated leukocytes and cytokines have important roles in the multisystem involvement during acute pancreatitis. The changes in the serum level of tumor necrosis factor-a (TNF-α) and interleukin-6 (IL-6) over time were investigated in two experimental acute pancreatitis models in rats. Mild edematous pancreatitis was induced with an overdose of cholecystokinin octapeptide (CCK-8), while a severe hemorrhagic form of pancreatitis was induced by ligation of the common bilio-pancreatic duct. The rats were examined 2, 4, 8, 16, 24 and 48 h after pancreatitis induction. The severity of the inflammation was assessed by measurement of the serum amylase activity, quantification of the edema, and histological examination. Serum TNF-α and IL-6 were determined by bioassay, using the TNF-sensitive WEHI 164 and the IL-6-dependent B9 cell lines, respectively. In CCK-8-induced acute pancreatitis, the pancreatic weight/body weight ratio (pw/bw) and amylase level were significantly elevated at 2 h, and the maximum levels were observed at 4 h (8.19±1.13 mg/g and 69.4±12.8×103 U/ml, respectively). Both parameters subsequently decreased continuously during the observation period. The serum IL-6 level was significantly increased at 4 h relative to the controls (123.3±5.8 vs 37.5±15 pg/ml), and then decreased continuously. In this model, only a moderate level of serum TNF-α was observed at 2 h. In the biliary type of acute pancreatitis, the ratio pw/bw increased continuously during the study and reached the maximum level at 48 h relative to the sham-operated control (8.8±1.4 vs 5.3±0.8 mg/g). The serum amylase level was significantly elevated at 2 h (43.2±13×103 U/ml), but then decreased continuously. The serum IL-6 reached its maximum level at 16 h (3800±447 pg/ml). In this model, increased TNF-α levels (75–300 U/ml) were measured 8, 16 and 24 h after pancreatitis induction. The results led to correlations between the serum IL-6 levels and the biochemical and morphological severity of acute pancreatitis in both experimental models. The data suggest that IL-6 and TNF-α may participate in the pathogenesis of these types of acute pancreatitis.