Jean-Paul Bernard

Endoscopic transpapillary drainage of pancreatic pseudocysts

BACKGROUND Endoscopic therapy of pancreatic pseudocysts has been reported mainly in small series. METHODS The results of endoscopic transpapillary cyst drainage (ETCD) were evaluated prospectively in 30 patients with pancreatic pseudocysts. RESULTS There were 24 men and 6 women with an average age of 45 years (SD 16). Twenty-eight had chronic pancreatitis (25 with alcoholic pancreatitis). Transpapillary cystopancreatic stents, with the tip into the cyst cavity, were inserted in 12 patients. Pancreatic stents with the tip as close as possible from the cyst cavity were inserted in the remaining 18 patients. Ten patients underwent an additional endoscopic cystenterostomy. The average duration of stenting was 4.4 months (range 15 days to 12 months). Patients were followed up for 15 months (range 2 to 60 months). All pseudocysts communicated with the pancreatic ductal system. The size of the pseudocysts ranged from 15 to 120 mm (average 50 mm). Pseudocysts were mainly located in the head of the pancreas (17 cases). Four minor complications occurred. There were no deaths. Twenty-six patients had pseudocyst resolution by ETCD, but 7 ultimately required surgery, 3 for early recurrence and 4 for failure of initial therapy. CONCLUSION ETCD appears to be a safe and efficient modality for the drainage of pancreatic pseudocysts communicating with the pancreatic ductal system.

Pancreas divisum is a probable cause of acute pancreatitis: a report of 137 cases.

The incidence of pancreas divisum (PD) was evaluated in a retrospective series of 1,825 successful consecutive ERCPs. One hundred thirtyseven pancreas divisums (7.5%) were found in 80 males and 57 females at a mean age of 49.2 years. The ventral ducts were visualized in 82.5% and the dorsal ducts in 74.1% of attempted cannulations of the minor papilla. Pancreas divisum was significantly more frequent in patients presenting with acute idiopathic pancreatitis (50.0%) or acute biliary pancreatitis (23.7%) than in controls or in the general population. This difference was not found in acute pancreatitis due to other etiologies. Acute pancreatitis associated with PD is generally recurrent, is not severe, but may be complicated by necrotic pseudocysts. The frequency of PD was also significantly increased in patients with gallbladder stones but not with common bile duct stones. In other pathological groups-chronic pancreatitis and pancreatic cancer-the frequency of pancreas divisum was not statistically different from that observed in controls and/or in the general population. We conclude that on a statistical basis, PD is a probable cause of acute pancreatitis, especially in its idiopathic recurrent variety, and that its frequency is increased in patients with gallbladder stones.

Chronic pancreatitis and inflammatory bowel disease: true or coincidental association?

OBJECTIVE:Several cases of pancreatitis have been described during the course of Crohns disease (CD) or ulcerative colitis (UC), but many of them were related to either biliary lithiasis or drug intake. We tried to evaluate the clinical and morphological features of so-called idiopathic pancreatitis associated with inflammatory bowel disease and to define their pathological characteristics.METHODS:Chronic idiopathic pancreatitis was diagnosed on the basis of abnormal pancreatograms suggestive of chronic pancreatitis associated with or without impaired exocrine pancreatic function, or pathological examination in patients undergoing pancreatic resection. We found 6 patients presenting with features of chronic idiopathic pancreatitis and UC and 2 patients with CD seen between 1981 and 1996 in three hospital centers of the south of France. A review of the literature has identified 6 cases of pancreatitis associated with UC and 14 cases of pancreatitis associated with CD based on the above criteria.RESULTS:Hyperamylasemia was not a sensitive test since it was present in 44% and 64% of patients with UC or CD. In UC, pancreatitis was a prior manifestation in 58% of patients. In contrast, the pancreatitis appeared after the onset of CD in 56% of the cases. In patients with UC, pancreatitis were associated with severe disease revealed by pancolitis (42%) and subsequent surgery. Bile duct involvement was more frequent in patients with UC than with CD (58%vs 12%) mostly in the absence of sclerosing cholangitis (16%vs 6%). Weight loss and pancreatic duct stenosis were also more frequent in UC than in CD (41%vs 12% and 50%vs 23%, respectively). Pathological specimens were analyzed in 5 patients and demonstrated the presence of inter- and intralobular fibrosis with marked acinar regression in 3 and the presence of granulomas in 2 patients, both with CD.CONCLUSIONS:Pancreatitis is a rare extraintestinal manifestation of inflammatory bowel disease. Chronic pancreatitis associated with UC differs from that observed in CD by the presence of more frequent bile duct involvement, weight loss, and pancreatic duct stenosis, possibly giving a pseudo-tumor pattern.

Mucinous ductal ectasia of the pancreas: a premalignant disease and a cause of obstructive pancreatitis.

Five cases of localized ectasiae of pancreatic ducts associated with epithelial mucinous metaplasia have been previously reported by Itai et al. (Radiology 1986;161:697–700). During a 1-year period, we collected four new observations of patients presenting with recurrent attacks of pancreatic pain due to similar clusters of cystlike dilated ducts communicating with the main pancreatic duct and lined by a columnar epithelium interspersed with numerous goblet cells. Duct lumina were filled with mucous. Carcinoembryonic antigen levels were high in the pure pancreatic juice, but normal in the blood. Sonography and CT scan showed cystlike, intrapancreatic defects localized three times in the head of the pancreas and once in the body. Endoscopic retrograde cholangiopancreatography (ERCP) showed a huge dilation of some collateral ducts filled by radiolucent defects. The main pancreatic duct was dilated proximally to pathological ducts in three cases. Neither pancreatic stones nor exocrine insufficiency could be demonstrated 7 years after the clinical onset; one case presented with an in situ carcinoma. Since mucinous ductal ectasia is a precancerous state, surgery is mandatory. ERCP is probably the best method of diagnosis.

Changes in Pancreatic Exocrine Secretion with Age: Pancreatic Exocrine Secretion Does Decrease in the Elderly

Pancreatic exocrine secretion was estimated in 180 normal control patients, free of abdominal and pancreatic disease, aged from 16 to 83 years. Duodenal juice was collected in two 15-min fractions after a single intravenous injection of 1 U/kg secretin + 3 U/kg CCK. Volume, maximal concentration and output of bicarbonate, lipase, phospholipase and chymotrypsin were estimated as well as minimal concentration and output of chloride and calcium. Each parameter was plotted against age, either individually or after separation into two age groups. Volume linearly increased up to the 3rd decade, and thereafter linearly decreased. Bicarbonate secretion paralleled fluid secretion and also decreased after the 3rd decade. The changes in chloride and calcium concentrations were different: concentrations linearly increased after the 3rd decade. Calcium concentration linearly increased with age (p less than 0.02) while chloride output was unchanged. The three enzymes that were studied linearly decreased in concentration as well as in output with age from the 3rd decade (p less than 0.02). Protein secretion decreased before water and bicarbonate secretion. One can conclude that pancreatic secretion changes in humans with age. Aging alters pancreatic secretion, through a decrease in flow rate, bicarbonate and enzyme secretion while calcium concentration is enhanced. Although not requiring substitutive therapy in the whole population, individual cases of pancreatic exocrine insufficiency might be explained by aging, without malnutrition.

Inhibition of Nucleation and Crystal Growth of Calcium Carbonate by Human Lithostathine

Pancreatic juice is naturally supersaturated in calcium and bicarbonate ions. A mechanism controlling CaCO3 crystal formation and growth is therefore necessary to prevent duct clogging. The present study shows that lithostathine, a glycoprotein present in human pancreatic juice at a concentration in the range of 10 mumol/L, could be involved in such a control. Lithostathine in concentrations greater than 1.5 mumol/L significantly delayed crystal nucleation and inhibited growth of preformed CaCO3 crystals from supersaturated solutions. Adsorption of lithostathine on crystals was shown by immunodetection. Albumin also adsorbed on CaCO3 crystals, but neither albumin nor other pancreatic secretory proteins inhibited crystal nucleation or growth. Lithostathine adsorbed to sites specifically inhibiting crystal growth with a dissociation constant (Kd) = 0.9 x 10(-6) mol/L. The glycosylated amino-terminal undecapeptide generated by limited trypsin hydrolysis inhibited CaCO3 crystal growth with a Kd = 3.0 x 10(-6) mol/L, similar to that of lithostathine. On the contrary, the carboxy-terminal polypeptide was inactive. A synthetic undecapeptide identical to the N-terminal end but not glycosylated was equally active. The activity disappeared upon digestion of the undecapeptide with V8 protease. The N-terminal undecapeptide of lithostathine is therefore essential to the inhibitory activity of the protein on CaCO3 crystal growth.

Regulation of proteolytic enzyme activities and mRNA concentrations in rat pancreas by food content.

Regulation by food content of the expression of genes encoding pancreatic proteases was studied in rats fed diets containing 15%, 25% or 70% protein (w/w) (diet I, II and III). Trypsin, chymotrypsin and elastase activities in pancreas were 1.4, 2.8 and 2 times higher in diet III than in diet I whereas carboxypeptidase A level was unchanged. As compared to diet I, the pancreatic concentration of mRNAs encoding trypsinogen I and chymotrypsinogen B, measured by filter hybridization to specific cDNA probes, were found respectively 3.6 and 3.9 times higher in diet III, and 1.9 and 2.6 times higher in diet II. Elastase I mRNA concentration was 1.8 times higher in diet III, but unchanged in diet II. Procarboxypeptidase A mRNA concentration was not affected. It is concluded to a coordinate pre-translational regulation of serine protease genes expression by the protein content of diet, differing however in amplitude and sensitivity among the three species of enzymes studied.

Pancreatic Stone Protein: Quantification in Pancreatic Juice by Enzyme-Linked Immunosorbent Assay and Comparison with Other Methods

To quantitate pancreatic stone protein (PSP), a competitive radio- immunoassay using monoclonal antibodies to PSP extracted from pancreatic stones and a sandwich enzyme-linked immunosorbent assay (ELISA) using monospecific polyclonal antibodies to the secretory forms of PSP (PSP S) were established. When PSP concentrations were measured in pancreatic juice by radioimmunoassay, no difference could be found between patients suffering from chronic calcifying pancreatitis and other diagnostic groups. Yet, with the ELISA technique involving polyclonal antibodies, decreased concentrations were found in chronic calcifying pancreatitis patients when compared to controls (p < 0.001), chronic alcoholics without pancreatic symptoms, or obstructive pancreatitis patients. These discrepancies are discussed. The monoclonal antibodies recognizing the C-terminal part of PSS S (PSP S1), results from the radioimmunoassay indicate that the concentration of that polypeptide is identical in the juice of controls and patients. Results from the ELISA obtained with polyclonal antibodies raised against PSP S2-5 molecules, i.e., recognizing the PSP S1 part and the N-terminal portion of the molecule, indicate that the differences observed reflect differences in the juice concentration of that N- terminal peptide.

Frequency and Characteristics of Pancreatitis in Patients with Inflammatory Bowel Disease

Background and Aims: Clinical symptoms of inflammatory bowel disease (IBD)-associated pancreatitis are found in ∼2% of patients, but the frequency of the disease could be much higher since IBD-associated pancreatitis could be mainly a silent disease. The aim of this study was to describe the radiological and biological features of IBD-associated pancreatitis and assess its frequency by comparing data from IBD patients with or without a history of pancreatitis. Methods: 79 patients were prospectively enrolled (median age 36 years). Symptoms of pancreatitis had been previously recorded in 30 of them (group P; the other 49 patients (group C) had no history of pancreatitis. Pancreatic ductal changes were investigated by pancreato-MRI. Exocrine function was assessed by the fecal elastase test and by assaying serum amylase, lipase, C-reactive protein, PAP, IgG4 and pancreatic autoantibodies. Results: Increased levels of amylase and lipase occurred in 11% of IBD patients, that frequency being significantly higher in group P (23%) than in group C (4%) (p = 0.01). Low fecal elastase reflecting impaired exocrine function was observed in 30% of patients and again significantly more in group P (50%) than in group C (17%) (p = 0.04). The frequency of elevated values varied from 12% for amylase and lipase to 18% for PAP, 20% for pancreatic autoantibodies and 45% for CRP, without a difference between groups P and C. Silent exocrinopathy was observed in both groups, pancreatic autoantibodies and pancreatic duct alterations being found in 20 and 11% of patients, respectively. Conclusion: Finding pancreatic insufficiency in about 30% of the included patients and in 50% of those with a previous history of pancreatitis suggests that IBD might be associated with chronic pancreatic alteration. Episodes of mild acute pancreatitis observed in some patients are not always due to adverse effects of treatments and can be acute manifestations of the chronic disease.

Biophysical Characterization of Lithostathine EVIDENCES FOR A POLYMERIC STRUCTURE AT PHYSIOLOGICAL pH AND A PROTEOLYSIS MECHANISM LEADING TO THE FORMATION OF FIBRILS

Lithostathine is a calcium carbonate crystal habit modifier. It is found precipitated under the form of fibrils in chronic calcifying pancreatitis or Alzheimer’s disease. In order to gain better insight into the nature and the formation of fibrils, we have expressed and purified recombinant lithostathine. Analytical ultracentrifugation and quasi-elastic light scattering techniques were used to demonstrate that lithostathine remains essentially monomeric at acidic pH while it aggregates at physiological pH. Analysis of these aggregates by electron microscopy showed an apparently unorganized structure of numerous monomers which tend to precipitate forming regular unbranched fibrils. Aggregated forms seem to occur prior to the apparition of fibrils. In addition, we have demonstrated that these fibrils resulted from a proteolysis mechanism due to a specific cleavage of the Arg11-Ile12 peptide bond. It is deduced that the NH2-terminal undecapeptide of lithostathine normally impedes fiber formation but not aggregation. A theoretical model explaining the formation of amyloid plaques in neurodegenerative diseases or stones in lithiasis starting from lithostathine is described. Therefore we propose that lithostathine, whose major function is unknown, defines a new class of molecules which is activated by proteolysis and is not involved in cytoskeleton nor intermediate filament functions.