László Czakó

Long-term outcomes of autoimmune pancreatitis: a multicentre, international analysis

Objective Autoimmune pancreatitis (AIP) is a treatable form of chronic pancreatitis that has been increasingly recognised over the last decade. We set out to better understand the current burden of AIP at several academic institutions diagnosed using the International Consensus Diagnostic Criteria, and to describe long-term outcomes, including organs involved, treatments, relapse frequency and long-term sequelae. Design 23 institutions from 10 different countries participated in this multinational analysis. A total of 1064 patients meeting the International Consensus Diagnostic Criteria for type 1 (n=978) or type 2 (n=86) AIP were included. Data regarding treatments, relapses and sequelae were obtained. Results The majority of patients with type 1 (99%) and type 2 (92%) AIP who were treated with steroids went into clinical remission. Most patients with jaundice required biliary stent placement (71% of type 1 and 77% of type 2 AIP). Relapses were more common in patients with type 1 (31%) versus type 2 AIP (9%, p<0.001), especially those with IgG4-related sclerosing cholangitis (56% vs 26%, p<0.001). Relapses typically occurred in the pancreas or biliary tree. Retreatment with steroids remained effective at inducing remission with or without alternative treatment, such as azathioprine. Pancreatic duct stones and cancer were uncommon sequelae in type 1 AIP and did not occur in type 2 AIP during the study period. Conclusions AIP is a global disease which uniformly displays a high response to steroid treatment and tendency to relapse in the pancreas and biliary tree. Potential long-term sequelae include pancreatic duct stones and malignancy, however they were uncommon during the study period and require additional follow-up. Additional studies investigating prevention and treatment of disease relapses are needed.

Involvement of oxygen-derived free radicals in L-arginine-induced acute pancreatitis

This study was aimed at an assessment of the role of oxygen-derived free radicals in the pathogenesis of L-arginine (Arg)-induced acute pancreatitis in rat, by measuring the levels of malonyl dialdehyde (MDA), glutathione peroxidase (GPx), catalase, and superoxide dismutase (Mn- and Cu,Zn-SOD) in the pancreatic tissue, and evaluating the protective effect of the xanthine oxidase inhibitor allopurinol. Acute pancreatitis was induced in male Wistar rats by injecting 2 × 250 mg/100 g body weight of Arg intraperitoneally in a 1-hr interval, as a 20% solution in 0.15 M NaCl. Control rats received the same quantity of glycine. Allopurinol, 100 or 200 mg/kg, was administered subcutaneously 30 min before the first Arg injection. Rats were killed at 6, 12, 24, and 48 hr following Arg administration, and acute pancreatitis was confirmed by a serum amylase level elevation and typical inflammatory features observed microscopically. The serum level of amylase reached the peak level at 24 hr after the Arg injection (30,800 ± 3813 vs 6382 ± 184 units/liter in the control) and normalized at 48 hr. The tissue concentration of MDA was significantly elevated at 24 hr and reached the peak value at 48 hr (5.00 ± 1.75 vs 0.28 ± 0.05 nM/mg protein in the control). The catalase and Mn-SOD activities were significantly decreased throughout the study, while the GPx activity was significantly reduced at 6 and 12 hr, and the Cu,Zn-SOD activity was significantly lower at 12 hr after the Arg injection as compared with the controls. Allopurinol treatment markedly reduced the serum amylase elevation (12.631 ± 2.257 units/liter at 24 hr) and prevented the increase in tissue MDA concentration (0.55 ± 0.09 nM/mg protein at 48 hr). Both doses of allopurinol significantly ameliorated the pancreatic edema, necrosis, and inflammation at 48 hr after Arg administration. Oxygen-derived free radicals are generated at an early stage of Arg-induced acute pancreatitis. Prophylactic allopurinol treatment prevents the generation of reactive oxygen metabolites, reduces the serum amylase concentration, and exerts a beneficial effect on the development of histopathological changes.

The role of nitric oxide in edema formation in L-arginine-induced acute pancreatitis.

Introduction Nitric oxide (NO) has been implicated in the regulation of the pancreatic circulation, the promotion of the capillary integrity, and the inhibition of leukocyte adhesion. Aims To investigate the rates of changes in the pancreatic constitutive NO synthase (cNOS) and inducible NOS (iNOS) activities and the role of NO in the vascular permeability changes during the development of L-arginine (Arg)–induced acute pancreatitis. Methodology Acute pancreatitis was induced in male Wistar rats by injecting 250 mg/100 g body weight of Arg i.p. twice at an interval of 1 hour, as a 20% solution in 0.15 M NaCl (group I). The control rats received the same quantity of glycine (group II). In group III, 30 mg/kg NG-nitro-L-arginine methyl ester (L-NAME) was injected i.p. 19 hours after the first Arg injection. The rats were killed at 6, 12, 24, or 48 hours following Arg administration, and the plasma amylase concentration and the pancreatic weight/body weight (pw/bw) ratios were evaluated. NOS activity was determined via the conversion of L-14C-Arg monohydrochloride to 14C-citrulline. The vascular permeability was examined by means of the extravasation of Evans blue dye (20 mg/kg bw) into the pancreatic tissue. Results The serum amylase level was already increased at 6 hours in group I animals, peaked at 12 hours after the Arg injection (11.800 ± 590 versus 6.618 ± 252 U/L in group II), and returned to the control level at 48 hours. The pw/bw ratio peaked at 24 hours in group I (6.63 ± 0.52 versus 4.02 ± 0.22 mg/g in group II) and returned to the control level at 48 hours. The cNOS activity was depleted at 6 hours in group I (0.02 ± 0.003 versus 0.23 ± 0.02 pmol/min/mg protein in group II); it then gradually increased to a level significantly higher than that in group II and decreased thereafter (0.45 ± 0.03 and 0.13 ± 0.01 pmol/min/mg protein at 24 and 48 hours). The iNOS activity was significantly increased at 24 and 48 hours versus that in group II (0.15 ± 0.05 and 0.07 ± 0.01 versus 0.04 ± 0.01 pmol/min/mg protein). The pancreatic concentration of Evans blue dye was significantly higher in group I than in group II (138.59 ± 11.04 versus 43.57 ± 2.67 (g/dry weight). Treatment with L-NAME significantly reduced the amylase activity, pw/bw, Evans blue concentration, and cNOS activity of the pancreas but did not exert any beneficial effect on the histologic score at 24 hours after the onset of pancreatitis, as compared with those values in group I (6.528 ± 673 U/L, 4.56 ± 0.65 mg/g, 86.84 ± 3.9 (g/dry weight, 0.14 ± 0.04 pmol/min/mg protein). Conclusion Endogenous NO is involved in the formation of pancreatic edema in Arg-induced acute pancreatitis by increasing the vascular permeability and protein extravasation. L-NAME treatment decreased the cNOS activity and edema formation but did not prevent the histologic damage in Arg-induced acute pancreatitis.

Interactions between the Endocrine and Exocrine Pancreas and Their Clinical Relevance

In consequence of the close anatomical and functional links between the exocrine and endocrine pancreas, any disease affecting one of these parts will inevitably affect the other. Pancreatic conditions which might cause diabetes mellitus include acute and chronic pancreatitis, pancreatic surgery, cystic fibrosis and pancreatic cancer. The development of diabetes greatly influences the prognosis and quality of life of patients with exocrine pancreatic diseases. It may cause life-threatening complications, such as hypoglycemia, due to the lack of glucagon and the impaired absorption of nutrients, or the micro- and macrovascular complications may impair the organ functions. Diabetes mellitus is an independent risk factor of mortality in those with exocrine pancreatic diseases. The treatment of pancreatic diabetes, a distinct metabolic and clinical form of diabetes, requires special knowledge. Diet and pancreatic enzyme replacement therapy may be sufficient in the early stages. Oral antidiabetic drugs are not recommended. If the diet proves inadequate to reach the glycemic goals, insulin treatment with multiple injections is required. Impairments of the exocrine pancreatic function and morphology in diabetic patients are frequent and well known. Atrophy of the exocrine tissue may be caused by the lack of trophic insulin, whereas pancreatic fibrosis can result from activation of stellate cells by hyperglycemia, or from microangiopathy and neuropathy. The regulation of the exocrine pancreatic function is also damaged because of the impaired effect of islet hormones. In the event of a proven impairment of the pancreatic exocrine function in diabetes mellitus, pancreatic enzyme replacement therapy is indicated. This may improve the nutritional condition of the patient and decrease the metabolic instability.

Quality of life assessment after pancreatic enzyme replacement therapy in chronic pancreatitis

GOALS To evaluate the quality of life (QoL) of patients with chronic pancreatitis before and after pancreatic enzyme replacement therapy in a prospective, multicentre, follow-up study. STUDY Two groups of patients were evaluated. Group 1 consisted of 31 patients with newly diagnosed chronic pancreatitis who had never been treated with pancreatic enzyme preparations. Group 2 consisted of 39 patients whose disease was diagnosed on average 3.4 years before the start of the study. The latter group of patients had undergone pancreatic enzyme replacement therapy, but during follow-up this treatment proved to be insufficient. The dose of pancreatic enzyme replacement therapy was tailored in accordance with the degree of pancreatic exocrine insufficiency measured by means of exocrine pancreatic function tests. A modified European Organizaton for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was used to assess QoL. RESULTS The social functioning and financial strain were significantly better, while the levels of hope and confidence were significantly reduced in group 1 compared with group 2. A significant gain in body weight and a significantly reduced defecation rate were found in both groups one month after the beginning of the pancreatic enzyme replacement therapy when compared with the pretreatment values. The prevalence of general and disease-specific symptoms and the intensity of pain were reduced in both groups after one month of enzyme substitution therapy. The working ability, the financial strain and the overall QoL scores were improved significantly in both groups, while the cognitive functioning score was found to be significantly improved during the follow-up only in group 1. The overall increase in the QoL score correlated significantly with the increase in body weight and the decrease in defecation number in both groups. CONCLUSIONS Pancreatic enzyme replacement therapy in patients with chronic pancreatitis not only reduced the extent of steatorrhea and pain, but also significantly improved a variety of other symptoms and the patients QoL. Individually tailored enzyme replacement therapy improved the QoL not only in the untreated chronic pancreatitis patients, but also in the inadequately treated group. This study demonstrated that the EORTC QLQ-C30 questionnaire, with the addition of two further questions about steatorrhea, is a useful tool for the evaluation of QoL in patients with chronic pancreatitis.

Diagnosis of early-stage chronic pancreatitis by secretin-enhanced magnetic resonance cholangiopancreatography

A diagnostic means of detecting chronic pancreatitis at an early stage, when the disease is still reversible, needs to be developed. Magnetic resonance cholangiopancreatography (MRCP) has recently been evolving as an important tool for the evaluation of chronic pancreatitis. In patients with moderate chronic pancreatitis, the pancreatic parenchyma displays an abnormal enhancement pattern on T1-weighted sequences after gadolinium administration. The presence of a signal intensity ratio of <1.7 in the arterial phase and/or delayed peak enhancement after contrast administration has a sensitivity of 92% and a specificity of 75% for the demonstration of early chronic pancreatitis. The secretin-induced pancreatic T2 signal intensity changes are significantly reduced in patients with a mild exocrine pancreatic insufficiency as compared with healthy volunteers. MRCP visualizes fluid in the pancreatic and biliary ducts as high signal intensity on heavily T2-weighted sequences. However, visualization of normal or minimally dilated pancreatic ducts by MRCP is more challenging because of their small size. Secretin administration stimulates fluid and bicarbonate secretion by the exocrine pancreas; consequently, it improves the pancreatic duct and side-branch delineation and allows an evaluation of the exocrine pancreatic function. Side-branch ectasia, mild ductal dilatation with loss of the normal gentle taper, and mural irregularities are the pathognomonic MRCP features of early-stage chronic pancreatitis. Through measurement of the duodenal filling, secretin-MRCP allows quantitative assessment of the exocrine pancreatic function, even in patients with a mild exocrine insufficiency. The morphology of the pancreatic ducts, particularly in the early stages, does not always correlate with the functional status. MRCP permits visualization of the ductal changes and furnishes functional information on the pancreas; this combination may enhance its diagnostic accuracy so that MRCP can become a valuable diagnostic means in early-stage chronic pancreatitis.

Oxidative stress in distant organs and the effects of allopurinol during experimental acute pancreatitis.

SummaryBackground. The present study was aimed at an assessment of the role of oxygen-derived free radicals in the development of local and systemic manifestations of l-arginine (Arg)-induced acute pancreatitis and at an evaluation of the protective effect of the xanthine oxidase inhibitor allopurinol.Methods. Acute pancreatitis was induced in male Wistar rats by injecting 2×250 mg/100 g body weight of Arg intraperitoneally at an interval of 1 h, as a 20% solution in 0.15 M NaCl. Control rats received the same quantity of glycine. In a third group, 200 mg/kg of allopurinol was administered subcutaneously 30 min before the first Arg injection. Rats were killed at 6, 12, 24, or 48 h following Arg administration. Acute pancreatitis was confirmed by a serum amylase level elevation and typical inflammatory features were observed microscopically. Tissue concentrations of malonyl dialdehyde (MDA), superoxide dismutase (Mn- and Cu,Zn-SOD), glutathione peroxidase (GPx), and catalase were measured in the pancreas, liver, and kidney.Results. The tissue concentration of MDA was significantly elevated in each organ. The activities of Mn-SOD, Cu,Zn-SOD, GPx, and catalase were quickly depleted in the pancreas and kidney, whereas only the Mn-SOD and GPx activities were reduced in the liver after the onset of pancreatitis. Histologic examination revealed acinar cell necrosis in the pancreas, but only mild alterations in the liver and kidney. Allopurinol pretreatment prevented the generation of reactive oxygen metabolites in the pancreas and reduced their formation in the kidney.Conclusion. Oxygen-derived free radicals are generated in the pancreas, liver, and kidney at an early stage of Arg-induced acute pancreatitis. The liver and the kidney, but not the pancreas, are able to defend against oxidative stress. The prophylactic application of allopurinol significantly restrains the generation of free radicals in pancreas and kidney.

Evaluation of pancreatic exocrine function by secretin-enhanced magnetic resonance cholangiopancreatography.

Aim To assess the feasibility and usefulness of secretin-enhanced magnetic resonance cholangiopancreatography (S-MRCP) for evaluation of pancreatic exocrine function. Methodology S-MRCP was performed in 20 patients with mild (n = 8) or severe (n = 12) chronic pancreatitis (according to the grade of exocrine pancreatic insufficiency indicated by the Lundh test) and in 10 volunteers without pancreatic disease. MRCP images were evaluated before and 10 minutes after the intravenous administration of 0.5 IU/kg secretin. The changes in pancreatic tissue T2 signal intensity and duodenal filling after the injection of secretin were determined by means of S-MRCP. The S-MRCP findings were then compared with those of the Lundh test. Results The pancreatic T2 signal intensity showed a significant elevation after secretin administration in the volunteers and in the patients with mild or severe chronic pancreatitis. This elevation was significantly lower in patients with mild and severe chronic pancreatitis than in the volunteers (66.85 ± 15.77 and 24.45 ± 5.85 vs. 200.0 ± 45.07, respectively). After administration of secretin, the diameter of the duodenum was significantly increased in all three groups. This duodenal filling was significantly reduced in patients with mild or severe exocrine pancreatic insufficiency as compared with the volunteers (4.12 ± 1.33 and 1.70 ± 0.77 vs. 15.38 ± 1.73, respectively). There was no significant difference in pancreatic T2 signal intensity changes or in duodenal filling in patients with mild or severe exocrine pancreatic insufficiency. There were significant correlations between the pancreatic T2 signal intensity changes and the duodenal filling and the results of the Lundh test (r = −0.616 and −0.78). Conclusion These results demonstrate that the administration of secretin increases the T2 signal intensity of the pancreatic tissue and the diameter of the duodenum to different extents in normal subjects and in patients with chronic pancreatitis. This suggests that S-MRCP can provide information of value in the assessment of an exocrine pancreatic insufficiency.

The pathogenesis of L-arginine-induced acute necrotizing pancreatitis: Inflammatory mediators and endogenous cholecystokinin

This study was aimed at an assessment of the role of oxygen-derived free radicals, cytokines and endogenous cholecystokinin (CCK) in the pathogenesis of L-arginine (Arg)-induced acute pancreatitis in rat. We measured the levels of malonyl dialdehyde (MDA), glutathione peroxidase (GPx), catalase and superoxide dismutase (Mn- and Cu, Zn-SOD) in pancreatic tissue, the serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and CCK, and evaluated the protective effect of the xanthine oxidase inhibitor allopurinol and a novel CCK receptor antagonist KSG-504. Acute pancreatitis was induced in male Wistar rats by injecting 2x 250 mg/100 g body weight of Arg intraperitoneally in an 1-h interval, as a 20% solution in 0.15 M NaCl. Control rats received the same quantity of glycine. 200 mg x kg(-1) allopurinol 30 min before the first Arg treatment or 50 mg x kg(-1) KSG-504 30 min before and 6, 18 and 36 h after the first Arg injection was administered subcutaneously. Rats were killed at 6, 12, 24 and 48 h following Arg administration, and acute pancreatitis was confirmed by a serum amylase level elevation and typical inflammatory features observed microscopically. The serum level of amylase reached the peak level at 24 h after the Arg injection (30,800 +/- 3,813 versus 6,382 +/- 184 U x L(-1) in the control) and normalized at 48 h. The tissue concentration of MDA was significantly elevated at 24 h, and reached the peak value at 48 h (5.00 +/- 1.75 versus 0.28 +/- 0.05 nM x mg(-1) protein in the control). The catalase and Mn-SOD activities were significantly decreased throughout the study, while the GPx activity was significantly reduced at 6 and 12 h, and the Cu, Zn-SOD activity was significantly lower at 12 h after the Arg injection as compared with the controls. Both the TNF-alpha and the IL-6 levels were already elevated significantly at 12 h and peak at 24 h versus the controls (19.1 +/- 7.9 U x mL(-1) and 57.6 +/- 11.2 pg x mL(-1) versus 3.1 +/- 0.8 U x mL(-1) and 15.2 +/- 3.1 pg x mL(-1), respectively). No significant changes in plasma CCK levels were observed. Allopurinol treatment markedly reduced the serum amylase elevation (12.631 +/- 2.257 U x L(-1) at 24 h), prevented the increase in tissue MDA concentration (0.55 +/- 0.09 nM x mg(-1) protein at 48 h) and significantly ameliorated the pancreatic edema, necrosis and inflammation at 48 h after Arg administration. KSG-504 administration did not exert any beneficial effect on the development of histopathological changes neither modified the serum amylase or cytokine levels. Oxygen-derived free radicals and cytokines are involved, while endogenous CCK does not seem to play a role in the pathogenesis of Arg-induced acute pancreatitis.

Randomised clinical trial: a 1-week, double-blind, placebo-controlled study of pancreatin 25 000 Ph. Eur. minimicrospheres (Creon 25000 MMS) for pancreatic exocrine insufficiency after pancreatic surgery, with a 1-year open-label extension

Pancreatic exocrine insufficiency (PEI) often occurs following pancreatic surgery.