[Endoscopy of the upper gastrointestinal tract]. / Endoskopie des oberen Gastrointestinaltrakts.

Esophagogastroduodenoscopy (EGD) has replaced X-ray diagnosis as the standard method for assessment of the upper gastrointestinal tract. It also offers an array of minimally invasive treatment options. This contribution presents the requisite medical, technical, and human resources needed for EGD. The indication for this invasive procedure should always be carefully reviewed and contraindications excluded. EGD should be performed according to standardized procedures and well documented by noting distinctive features of peristalsis and describing alterations of mucosal size and surface texture. The endoscopic techniques of biopsy, chromoendoscopy, and percutaneous endoscopic gastrostomy should always be available in routine endoscopy.

[Pyogenic liver abscess in chronic alcoholic pancreatitis]. / Pyogener Leberabszess bei chronischer äthyltoxischer Pankreatitis.

HISTORY AND ADMISSION FINDINGS: A 44-year-old patient was transferred for further treatment of pyogenic liver abscess and a severe attack of a chronic pancreatitis for strong upper right quadrant abdominal pain and recurring fever. INVESTIGATIONS: Laboratory results revealed a significant inflammatory constellation. Abdominal ultrasound was performed which showed a big pyogenic abscess in the right lobe of the liver. Escherichia coli and Enterococcus faecalis could be isolated from abscess aspirates. Endoscopic retrograde cholangiography (ERC) without access of the pancreatic duct showed stenosis of the Ductus hepatocholedochus which was treated with a biliary endoprothesis. DIAGNOSIS, TREATMENT AND COURSE: Antibiotic treatment and percutaneous drainage led to complete remission of the abscess. A few days after discharge the patient returned with identical clinical symptoms. Abdominal ultrasound showed recurrence of the abscess. Because of excessively high pancreatic amylase in aspirated abscess material the patient underwent endoscopic retrograde cholangiopancreaticography (ERCP). There, a pancreatico-hepatic fistula was seen, probably the result of necrosis caused by a severe acute attack of the chronic pancreatitis. After insertion of a naso-fistular drainage, continous rinse and appropriate antibiotic therapy both abscess and fistula completely disappeared without recurrence. CONCLUSION: The rare case of a pancreatic fistula should be considered when a pyogenic liver abscess follows an episode of acute pancreatitis or attack of chronic pancreatitis. Determination of pancreatic amylase in aspired abscess material can be an important step towards correct diagnosis.

[Changes in incidence and prevalence of acute and chronic pancreatitis in Germany]. / Incidenz- und Prävalenzveränderungen der akuten und chronischen Pankreatitis in Deutschland.

It is difficult to provide valid data with regard to changes in incidence and prevalence of acute pancreatitis in Germany. The lack of information is due to strict legal regulations to protect personal data, a certain lack of interest in epidemiological research and the lack of exact statistics of diseases treated in hospitals. The incidence of acute pancreatitis in other industrialized Western countries is about 10 new cases per year and 100,000 inhabitants. The increase of alcohol consumption over the last 30 years is associated with an increase of ethanol-induced pancreatitis. One may speculate that due to improved diagnostic possibilities, such as CT scan, cases where acute pancreatitis is diagnosed at autopsy are rare. Due to the increase in alcohol consumption it can be assume that the incidence and prevalence of chronic pancreatitis have increased in Germany similar to well-documented data from Denmark. Since alcohol consumption is slightly decreasing in Germany it is likely that the present incidence of about 10 cases of chronic pancreatitis per 100,000 inhabitants will also decrease.

Apolipoprotein A-I in bile inhibits cholesterol crystallization and modifies transcellular lipid transfer through cultured human gall-bladder epithelial cells.

BACKGROUND: Apolipoprotein A-I (Apo A-I), conventionally purified by several steps including organic solvent-delipidation from plasma, inhibits cholesterol crystallization in bile. To observe a significant effect in vitro, however, supraphysiological concentrations above 100 microg/mL are required. For this reason, this protein has not been considered to play a physiological role in vivo. In the present study, we examined the cholesterol crystal growth-inhibiting effect of biliary Apo A-I at its physiological concentration, the modification of transcellular transfer of biliary lipids through cultured human gall-bladder epithelial cells (GBEC) by Apo A-I at its physiological concentration and the binding and secretion of Apo A-I by GBEC. METHODS AND RESULTS: We purified biliary Apo A-I to near homogeneity using immobilized artificial membrane chromatography. At 5 microg/mL, biliary Apo A-I reduced cholesterol crystal mass by 50%, whereas plasma-derived, solvent-delipidated Apo A-I had no effect. Using an antibody-capture enzyme-linked immunosorbent assay, we found reduced Apo A-I concentrations in bile samples from gallstone patients when compared with bile samples from gallstone-free controls (medians, 2.35 and 9.4 microg/mL, respectively). In a GBEC line, Apo A-I (5 microg/mL) enhanced transfer of phospholipid and cholesterol from the mucosal to the serosal side of cell monolayers by approximately 50%. These cells appear to bind Apo A-I reversibly in a dose- and time-dependent manner, compatible with receptor-type binding. Cultured human gall-bladder epithelial cells also showed basal secretion of Apo A-I, which was greatly increased by exposure to model bile solutions. CONCLUSIONS: Apolipoprotein A-I in bile, thus, has both a direct effect on cholesterol crystal formation and enhances lipid removal from gall-bladder bile by GBEC. This effect may be specific and receptor mediated. These observations support two separate roles for human biliary Apo A-I and suggest that this protein may be important in preventing the formation of cholesterol crystals (the initial step in gallstone formation) in supersaturated bile.

Primary amyloidosis of the mesentery and the retroperitoneum presenting with lymphedema.

We report the case of a 57-yr-old woman presenting with moderate weight loss, abdominal distension, and lymphedema of the legs and vulva. Computed tomography of the abdomen revealed massive thickening of the rectal wall, mesentery, and retroperitoneum. Primary amyloidosis was diagnosed by immunohistochemistry from the rectum and duodenum. To our knowledge, lymphedema due to primary amyloidosis has not yet been reported. The diagnosis should be presumed in the case of retroperitoneal thickening and lymphedema and can be established by immunohistochemistry.

[Role of biliary proteins in pathogenesis of cholesterol gallstones]. / Die Rolle biliärer Proteine in der Pathogenese von Cholesteringallensteinen.

Cholelithiasis is a frequent disease in developed countries with significant economical implications. While the multifactorial pathogenesis of cholesterol gallstones has been widely accepted, the relative importance of the various contributing factors is not yet clear. One focus of research in recent years has been the identification and functional analysis of biliary proteins. Few proteins are synthesized in the biliary tract itself, the majority reflect the composition of serum proteins. Many biliary proteins modify cholesterol crystallization, the initial step of cholesterol gallstone formation. In cholelithiasis, biliary concentration of many pronucleating proteins are increased. However, this may be a consequence rather than the cause of the disease, because a majority of these proteins are acute-phase reactants. They may be secreted into bile at increased concentrations because of--often asymptomatic--cholecystitis due to gallstone disease. A number of protein-lipid interactions have been observed in search of a mechanism of action of biliary effector proteins. Only recently the potential modification of lipid removal from gallbladder bile by Apo A-I was described in addition to its direct antinucleating effect. In conclusion, biliary proteins directly modify cholesterol crystallization by protein-lipid interactions and may influence lipid absorption from the gallbladder.

Comparison of haptoglobin and apolipoprotein A-I on biliary lipid particles involved in cholesterol crystallization.

Several proteins are known to modulate cholesterol crystallization. We recently demonstrated that haptoglobin has cholesterol crystallization promoting activity. However, this effect is still not well understood mechanistically. The current study examined the distribution of haptoglobin compared to apolipoprotein A-I (apo A-I) to micelles, vesicles and crystals as an initial step in providing a focus for further studies of the mechanism of cholesterol crystallization activity. Specific protein purification was accomplished by immunoaffinity chromatography. The crystallization-promoting activity of biliary haptoglobin, albumin and commercial apo A-I was measured by a photometric crystal growth assay. The distribution of micelles, vesicles and proteins in model bile was determined by Sepharose CL-6B column chromatography. Detection of the presence of test proteins in cholesterol crystals was determined using specific 125I-radiolabelled proteins. Haptoglobin (20 micrograms/mL) showed a significant crystallization promoting-activity, whereas apo A-I (30 micrograms/mL) only tended to show a slight inhibitory activity. The cholesterol crystal-bound protein in each case was found to be less than 1% of the total concentration of that protein that had been added to the model bile system. The elution profile of commercial apo A-I from a Sepharose CL-6B column was strikingly altered when it was added to model bile prior to elution. In contrast, the column elution profiles for both haptoglobin and albumin were unchanged when model bile was similarly added to the sample. Haptoglobin increased the amount of cholesterol found in the vesicular fraction when compared to apo A-I. Haptoglobin does not bind tightly to either biliary lipid particles or to cholesterol crystals but does increase the amount of cholesterol in vesicles by inducing a shift from micellar cholesterol (P = 0.046). This shift appears to explain in part its promoting effect on cholesterol crystallization.

Purification and characterization of a novel human 15 kd cholesterol crystallization inhibitor protein in bile.

Crystallization-inhibiting proteins can explain longer nucleation times associated with bile from gallstone-free subjects as compared with bile from patients with cholesterol gallstones. We partially characterized and examined the crystallization inhibitory potency of a newly purified 15 kd human biliary protein. Gallbladder bile was passed through an anti-apolipoprotein A-I (apo A-I) immunoaffinity column to extract lipid-associated proteins. The bound fraction was separated by 30 kd ultrafiltration. Sodium dodecyl sulfate-polyacrylamide gel electrophesis (SDS-PAGE) was performed under nonreducing and reducing conditions. Cholesterol crystallization activity was tested in a photometric cholesterol crystal growth assay. Isoelectric focusing was performed by using a standard gel. The purified 15 kd protein was subjected to N-terminal amino acid sequencing. Although the whole apo A-I-bound fraction contained a variety of proteins and lipids, its 30 kd filtrate yielded a nearly pure 15 kd protein with only minor contamination from apo A-1. Amino acid sequencing showed that the protein was unique. Enzymatic deglycosylation revealed no evidence for glycosylation. At a protein concentration of 10 micrograms/ml, crystallization time was delayed as compared with control and apo A-I, and final crystal mass was reduced to 75% of control. Its isoelectric point was 6.1 without isoforms. Under nonreducing conditions, the protein formed a 30 kd dimer and a 60 kd tetramer. We conclude that this protein is a novel potent biliary crystallization inhibitor protein.

Biliary haptoglobin, a potent promoter of cholesterol crystallization at physiological concentrations.

BACKGROUND/AIMS: Several proteins present in human bile have been reported to promote cholesterol crystallization and thus are potentially important in the formation of cholesterol crystals as the initial stage in gallstone pathogenesis. To be physiologically relevant, such proteins must either be present in high concentration in bile or have a potent promoting activity. The current study explored several of the more abundant but unexamined biliary proteins based upon their also having sufficiently high serum concentrations that antibodies were available for both their isolation and quantitation. METHODS: Protein purification was accomplished by immunoaffinity chromatography of bile followed by delipidation. Con A affinity chromatography of bile was used to obtain the bound fraction, a portion of which was delipidated. Crystallization-promoting activity of both the purified proteins and Con A-bound glycoprotein fractions (CABG) was measured by a photometric crystal growth assay. A competitive antibody-capture ELISA assay was developed to measure concentrations of alpha 1-antitrypsin, transferrin, and haptoglobin in native bile. RESULTS: At their relevant physiological concentrations, biliary haptoglobin (15 micrograms/ml) had a crystallization-promoting activity twice that of the biliary IgM (75 micrograms/ml) used as a reference standard (P < 0.05). Biliary transferrin (20 micrograms/ml) had only modest promoting activity (P < 0.05). Biliary alpha 1-antitrypsin (50 micrograms/ml), by contrast, showed no promoting activity. Delipidation of the CABG fraction decreased its promoting activity by 75%. Biliary haptoglobin accounts for about 30% of delipidated total CABG-promoting activity. CONCLUSIONS: Biliary haptoglobin at its physiological concentration has a highly potent crystallization-promoting activity and thus becomes a candidate for major attention in understanding gallstone pathogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of phospholipase A2 in pancreatic acinar cell damage and possibilities of inhibition: studies with isolated rat pancreatic acini.

Phospholipase A2 (PLA2) has been postulated to play an important role in the pathogenesis of acute pancreatitis. To study the mechanism through which PLA2 may cause cellular damage, we used an in vitro model of isolated rat pancreatic acini prepared by collagenase digestion. Newly synthesized proteins were labeled by [35S]methionine. Cellular destruction was measured by the degree of release of radiolabeled proteins. Incubation of pancreatic acini with PLA2 alone caused only minor damage when very high concentrations of this enzyme were used. However, when acini were incubated with PLA2 in combination with its substrate, lecithin, cells were destroyed in a time- and concentration-dependent manner. Incubating cells with pancreatic homogenates and lecithin caused damage only when there had been prior activation of homogenates with either trypsin or enterokinase. The damage could be simulated by incubating acini with pure lysolecithin. Alcohol and cerulein did not further increase the destruction caused by PLA2 and lecithin. When acini were incubated with supernatants from another set of acini to which oleic acid had been added, a similar degree of damage resulted as compared with acini incubated with oleic acid alone. However, adding PLA2 to supernatants from acini preincubated with fatty acids significantly increased the degree of cellular necrosis. The destruction by PLA2 and lecithin was inhibited by albumin but could not be inhibited by gabexate mesilate, nafamostat mesilate, or cytidine diphosphocholine. We conclude that PLA2 could play a role in pancreatic acinar cell damage, especially in the spread of cellular necrosis within the organ, provided that its substrate, lecithin, is present.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of pain with pancreatic extracts in chronic pancreatitis: results of a prospective placebo-controlled multicenter trial.

According to the theory of negative feedback regulation of pancreatic enzyme secretion by proteases, treatment with pancreatic extracts has been proposed to lower pain in chronic pancreatitis by decreasing pancreatic duct pressure. We conducted a prospective placebo-controlled double blind multicenter study to investigate the effect of porcine pancreatic extracts on pain in chronic pancreatitis. 47 patients with pain (41 males, 6 females) due to chronic pancreatitis documented by sonography, endoscopic retrograde cholangiopancreatography, and CT were included. Exclusion criteria were steatorrhea above 30 g/day, gastric or pancreatic resections in the history, and serum bilirubin above 1.5 mg/dl. Patients received pancreatic extracts (acid-protected microtablets; Panzytrat -20,000; 5 x 2 capsules/day; proteases/capsule 1,000 Pharmacopoea europaea units) for 14 days followed by treatment with placebo for another 14 days or vice versa. Pain (graded from 0 to 3) and concomitant use of analgesics (N-butylscopolaminiumbromide and tramadol) were recorded by diary. Physical examination and blood chemistry were done at day -1, 15 and 29. Quantitative stool fat was determined at days -2/-1, 13/14 and 27/28. 43 patients completed the studies. Pain improved in most patients irrespective of whether they started with placebo or verum. There was no significant difference between both treatment arms. We conclude that pancreatic extracts are not very efficient in lowering pain.

Prostaglandin E2 inhibits secretagogue-induced enzyme secretion from rat pancreatic acini.

Prostaglandins of the E type may have a potential role in pancreatic physiology and pathophysiology. Because prostaglandins of the E type inhibit HCl secretion in parietal cells via a specific receptor by inhibition of adenylylcyclase, we studied whether a similar mechanism exists in the exocrine pancreas. Isolated rat pancreatic acini were incubated with various concentrations of secretagogues, such as cholecystokinin-octapeptide (CCK-8), bombesin, carbachol, and vasoactive intestinal peptide (VIP), in the absence or presence of prostaglandin E2 (PGE2), and amylase secretion was measured. For receptor binding studies, acini and pancreatic membranes were incubated with [3H]PGE2 and either unlabeled PGE2 or other types of prostaglandins. PGE2 (10(-13) to 10(-5) M) did not inhibit basal amylase secretion. However, CCK-8-stimulated secretion was significantly inhibited. Stimulation of secretion by bombesin, carbachol, VIP, and secretin was also inhibited by PGE2, but not as pronounced as CCK-8-stimulated secretion. The formation of inositol 1,4,5-trisphosphate induced by CCK-8 was markedly inhibited by simultaneous incubation with PGE2. Furthermore, PGE2 slightly but significantly reduced the CCK-8-induced efflux of 45Ca2+ from prelabeled acini. Intact acini and a membrane fraction bound [3H]PGE2 and this function could be equally competed by either unlabeled PGE2 or PGE1 in contrast to less-related prostaglandins such as PGF2 alpha, PGD2, and prostacyclin. We conclude that prostaglandins of the E type inhibit pancreatic enzyme secretion stimulated by various secretagogues. This function is mediated via specific receptors for PGE. With regard to CCK-8-stimulated secretion this function may be mediated by an inhibition of formation of inositol 1,4,5-trisphosphate.

Comparison between the synthetic cholecystokinin analogues caerulein and Thr28NlE31CCK25-33(CCK9) with regards to plasma bioactivity, degradation rate and stimulation of pancreatic exocrine function.

A new synthetic analogue of cholecystokinin, Thr28Nle31CCK25-33(CCK9) is compared with caerulein with regards to plasma bioactivity, degradation rate, side effects, and stimulation of pancreatic secretion. 24 healthy male volunteers were intubated with a double lumen Lagerlöf-tube. 30 min after correct positioning of the tube subjects received a continuous intravenous infusion of synthetic secretin (1 U/kg) together with either ceruletide (61.5 pM/kg) or CCK9 (30 pM/kg) both for 45 min. 30 pM/kg of CCK9 have been shown by others to cause maximal enzyme secretion (1). 61.5 pM/kg (= 100 ng) of caerulein are probably supramaximal but used by many centers for direct pancreatic function tests. Plasma CCK was measured by bioassay which compares amylase release of isolated rat pancreatic acini stimulated by plasma extracts with known standards of CCK8. Lipase, amylase, trypsin, chymotrypsin, and bicarbonate were measured in 15 min fractions after the onset of CCK infusion. Both drugs caused a similar stimulation of pancreatic enzyme secretion during infusion of the respective analogue which declined after termination. After the onset of CCK9 infusion plasma bioactivity reached a plateau around 20 pM at 15 min. Values declined after 30 min. After termination of infusion bioactivity rapidly declined within 3 min but still remained slightly elevated after further 15 min as compared to basal values (3.9 vs 0.6 pM). Plasma kinetics of caerulein were quite similar. However, despite a dose which was only twice as high as compared to CCK9, plasma bioactivity was six times higher with plateau values of about 120 pM.(ABSTRACT TRUNCATED AT 250 WORDS)

Pancreatic enzyme synthesis and secretion are independently regulated by insulin and glucocorticosteroids.

Both insulin and glucocorticosteroid (GS) deficiency causes a reduction of amylase synthesis and changes in the dose-response curve of cholecystokinin (CCK) stimulated enzyme secretion in rats. Since we found a reduction of plasma insulin in adrenalectomized rats, we now tested the hypothesis that the regulation of amylase synthesis by insulin may be mediated by GS. Three groups of male rats were investigated: controls, streptozotocin induced diabetics, and diabetics treated with GS. Animals were sacrificed 10-14 days after injection of streptozotocin and isolated pancreatic acini prepared by collagenase digestion. Protein synthesis was measured on the translational level by incubation of acini with 35S-methionine followed by lysis of cells and separation of proteins by SDS-PAGE. In addition, protein synthesis was measured on the transcriptional level by isolation of mRNA from pancreatic acini and translation of proteins using the rabbit reticulocyte lysate system. The loss of insulin in diabetic rats was associated with a 70-90% decrease in amylase synthesis and increases of synthesis of various proteases. This was due to a specific decrease in mRNA coding for amylase and increase in mRNA coding for proteases. Furthermore, the known rightward shift of the dose response curves of CCK stimulated amylase secretion was seen in diabetic animals. Treatment of diabetic rats with GS did deteriorate the catabolic status seen in diabetes with increases in mortality as compared to diabetes alone. However, neither the overall pattern of enzyme synthesis seen in diabetic rats nor the alterations in CCK stimulated enzyme secretion were changed by treatment with GS. We conclude that the regulation of amylase synthesis and enzyme secretion by insulin is not mediated via GS.