[Endoscopic therapy for leaks in the gastrointestinal tract, the bile ducts and the pancreas]. / Endoskopische Therapie von Leckagen im Gastrointestinaltrakt, an den Gallenwegen und im Pankreas.

Surgery has been the mainstay of therapy in patients with gastrointestinal perforations, leakage or fistulas. New techniques for endoscopic closure of gastrointestinal perforations provide tools for an effective treatment by less invasive procedures. Temporary placement of covered self-expanding stents is an established therapy for oesophageal perforations and anastomotic leaks. Using conventional endoclips small perforations and leaks in the oesophagus and gastrointestinal tract may be closed. With the new over-the-scope-clips a more effective endoscopic full wall closure is possible in the upper gastrointestinal tract and the rectum. Endoscopically guided endoluminal vacuum therapy using polyurethane sponges is an established method for treating rectal leaks and is now increasingly used also in oesophageal leaks. Biliary leakage following endoscopic or surgical interventions is effectively treated with temporary bile stenting in most cases, but closure using metal stents or coiling may be necessary. Pancreatic leaks are a major therapeutic problem and may require multimodal therapies.

[Multiple bilateral pulmonary nodes following breast cancer]. / Multiple bilaterale Lungenrundherde nach Mammakarzinom.

HISTORY AND ADMISSION FINDINGS: Multiple new pulmonary nodules were demonstrated at chest radiography in a 69-year-old woman who had been treated for breast cancer ten years previously. INVESTIGATIONS: Laboratory tests suggested mild inflammation. Pulmonary function tests demonstrated small airways disease. But because of an atypical morphology at computed tomography (CT), metastases were considered unlikely. CT-guided percutaneous biopsy revealed cryptogenic organizing pneumonia (COP). TREATMENT AND COURSE: Oral medication with decreasing doses of steroids resulted in clinical and radiological improvement. CONCLUSIONS: Even in a patient with known malignancy the differential diagnosis of multiple bilateral pulmonary nodules includes a variety of conditions and is meticulous, if necessary invasive diagnostic procedures are required.

Solitary pulmonary nodule with growth and contrast enhancement at CT: inflammatory pseudotumour as an unusual benign cause.

Small (< or =10 mm) pulmonary nodules are frequently detected at modern chest CT. As most of these nodules are benign, non-invasive classification is required--usually based on assessment of growth and perfusion. Absence of growth and no evidence of perfusion, as demonstrated by lack of enhancement at contrast-enhanced CT or MRI, strongly suggest a benign nodule. On the other hand, growth with a doubling of the nodule's volume between 20 days and 400 days or enhancement suggest a malignant nature of the lesion. We present an example of a nodule with strong contrast enhancement and a doubling time of approximately 260 days, which histologically represented a benign inflammatory pseudotumour.

[Transjugular intrahepatic portosystemic stent shunt: indications and long-term outcome]. / Transjugulärer intrahepatischer portosystemischer Stent-Shunt: Indikationen und Langzeitresultate.

The transjugular intrahepatic portosystemic stent shunt has replaced surgical shunt procedures as the standard therapy for complications of portal hypertension such as refractory ascites and recurrent variceal bleeding. However, reinterventions due to TIPS stenosis are necessary in 25-50 %. Major complications are the manifestation or worsening of hepatic encephalopathy. Recent studies using PTFE covered stents have shown lower stenosis rates and a trend towards prolonged survival.

Lack of portosystemic bacterial translocation in patients with liver cirrhosis after placement of transjugular shunt.

The purpose of this study was to clarify whether bacteria are transferred from the portal venous system into central venous blood during the placement of a transjugular portosystemic stent shunt (TIPSS). TIPSS was created in 30 consecutive cirrhotic patients for recurrent variceal bleeding ( n=12), refractory ascites ( n=16), or hepatorenal syndrome ( n=2). Microbiological analysis was performed prospectively on central venous blood before and on portal venous blood immediately after puncture of the portal vein. Twenty minutes after the placement of TIPSS, another sample of central venous blood was obtained. None of the first two sets of blood cultures showed bacterial growth, so that no bacterial transfer was seen at the time of TIPSS placement. Four of the third sets of blood samples showed skin and mouth flora, interpreted as iatrogenic contamination.

[Predictive parameters of infectiologic complications in patients after TIPSS]. / Prädiktive Parameter infektiologischer Komplikationen bei Patienten nach TIPSS-Anlage.

AIM: To define predictive parameters of a complicated clinical course after the TIPSS procedure. METHODS: Blood cultures were drawn prospectively in 41 patients from a central line and from the portal venous blood before stent placement as well as from the central line 20 min after intervention. C-reactive protein (CRP) (mg/dl) and white blood cell count (WBC,/microl) on the day of TIPSS-procedure (d0), the first (d1) and seven (d7) days after TIPSS were compared in patients with a complicated clinical course (spontaneous bacterial peritonitis,pneumonia,sepsis; group I) to patients without clinical complications (group II) RESULTS: Group I showed a significant increase in CRP (d0: 1.8+/-1.0; d1: 3.2+/-1.5; d7: 4.3+/-3.2), and white blood cell count (d0: 7700+/-2600; d1: 10800+/-2800; d7: 7500+/-1800) on the first day after TIPSS-procedure in comparison to group II (CRP: d0: 1.6+/-0.6; d1: 1.8+/-1.0; d7: 1.9+/-0.6. WBC: d0: 6900+/-1500; d1: 8000+/-1600; d7: 7600+/-1400). Microbiological analysis showed in 12% skin or oral flora in the last sample. CONCLUSIONS: The course of CRP and WBC-count during the first week after TIPSS procedure may indicate patients with a potential risk of a complicated clinical course.

CT and MRI findings of multifocal hepatic steatosis mimicking malignancy.

We present two rare cases of multifocal hepatic steatosis as a variant of fatty liver. Multifocal hepatic steatosis can cause misleading findings in the differential diagnosis when using ultrasound and computed tomography. This case report describes the atypical findings of focal fatty liver infiltrations, which were misdiagnosed as diffuse metastatic disease. The correct diagnosis was established with magnetic resonance imaging using T1-weighted gradient-echo and T2-weighted Turbo spin-echo sequences with spectral fat suppression. Multifocal hepatic steatosis was proven by biopsy.

Long-term results following different extent of resection in chronic pancreatitis.

BACKGROUND/AIMS: To evaluate, whether the indication related varying extent of resection in chronic pancreatitis has a predictable impact on long-term outcome. METHODOLOGY: One hundred and twenty-six patients consecutively underwent surgery for chronic pancreatitis from March 1987 to September 1997. Three treatment categories were defined: Pancreatoduodenectomy, duodenum-preserving resection and drainage procedures, and left-sided pancreatectomy. Main outcome measures were late mortality, pain scores preoperatively and at follow-up, body-weight change, percentage of insulin dependent diabetes, patient's and physician's satisfaction with surgery. RESULTS: Forty-one patients underwent pancreatoduodenectomy, 59 drainage procedures, and 26 left-sided pancreatectomy, respectively. Hospital mortality was 1 (2.4%), 4 (6.8%), and 1 (3.8%) (P = NS), totaling 4.8%. After an average follow-up of 5.2 years, late mortality was 10 (24.4%), 9 (15.3%), and 4 (15.4%) (P = NS) for a total of 23 (18.3%). Two patients (1.6%) died of unsuspected pancreatic cancer. Three patients (2.4%) had to be reoperated upon for pain relapse. The mean pain score was 8.8 preoperatively and 2.1 at late follow-up and not different among groups. Body-weight gain averaged 3.0, 4.0, and 3.4 kg, with no significant differences. Percentage of insulin dependency in all patients rose from 14% prior to surgery to 30% at reevaluation, and was very similar in all treatment categories. CONCLUSIONS: The different kind and level of invasiveness of the surgical procedures did not significantly influence the late outcome. High rates of late mortality and deterioration of endocrine function are to a greater extent sequelae of comorbidity and the progression of the underlying pancreatic disease.

Menadione-induced oxidative stress inhibits cholecystokinin-stimulated secretion of pancreatic acini by cell dehydration.

The present study evaluated the effects of free radicals generated by menadione on morphology and function of pancreatic acinar cells focusing on enzyme secretion, stimulus-secretion coupling, and cell hydration. Various experiments evaluated morphology and function of isolated rat pancreatic acinar cells exposed to menadione. Menadione instantaneously generated free radicals (luminol and deoxyribose assays) followed by a time-dependent cell injury (uptake of trypan blue). Early ultrastructural changes included vacuolization and alterations of mitochondria, endoplasmic reticulum, and nucleus. Menadione caused a rapid glutathione oxidation followed by a depletion in reduced glutathione. An increase in lipid peroxides and a depletion of adenosine triphosphate were seen only after 30-60 minutes. Menadione markedly inhibited amylase release stimulated by cholecystokinin (CCK) and carbachol and simultaneously caused cell shrinkage after a few minutes. Similar degrees of cell shrinkage induced by hyperosmolar incubation and by menadione inhibited amylase secretion to a similar extent. CCK binding and its effect on calcium and inositol 1,4,5-trisphosphate (IP3) were not affected by menadione. Menadione (without CCK) induced an instantaneous increase of intracellular calcium followed by a slow constant increase. In single cells, menadione induced calcium oscillations with a frequency lower than that seen after CCK stimulation. Some morphologic and functional alterations owing to menadione-induced oxidative stress may be caused by adenosine triphosphate and glutathione depletion, lipid peroxidation, and changes in cytosolic calcium. The marked inhibition of secretagogue-stimulated enzyme secretion owing to menadione may be mediated to a large part by cell dehydration, whereas classical steps of stimulus-secretion coupling like receptor binding, calcium release, and IP3 generation remained unchanged.

[Gastroenterology diagnosis of pancreatic carcinoma]. / Die gastroenterologische Diagnostik des Pankreaskarzinoms.

Abdominal ultrasound is the primary imaging study for patients with suspected pancreatic carcinoma. Unless the tumor is large, this test might not be abnormal. The next appropriate test in the diagnostic work-up is the EUS. If this technique is not available, dual-phase spiral CT might be ordered instead. In cases which remain unclear or require palliative relief of biliary obstruction. It has been proposed that diagnosis and staging of a pancreatic carcinoma can be afforded by an all-in-one investigation using MRI, MRCP and MR-angiography. But at present, the superiority of MRI for diagnosing pancreatic cancer is insufficiently established. Conventional angiography does no longer play a role in the staging process. Fine-needle aspiration of focal pancreatic lesions is only recommended in patients who have unresectable lesions or who are more likely to have a focal inflammatory lesion in chronic pancreatitis. Laparoscopy is indicated if there is a high likelihood of unrecognized peritoneal or hepatic micrometastases in patients who are otherwise candidates for a surgical cure. Furthermore, laparoscopy should only be performed if the proof of metastases precludes further surgery or if palliative surgery is not necessary. Tumor markers and genetic markers might help to detect pancreatic cancer. However, the optimal screening method for the diagnosis of early and potentially curable pancreatic cancer is not in sight as yet.

Oxidative stress in acute pancreatitis.

The present work critically reviews the evidence for an involvement of free radicals in the pathophysiology of acute pancreatitis and the potential of treatment with antioxidants and scavenger substances. Data originating from clinical trials, experimental pancreatitis studies and in vitro investigations are included. Enhanced free radical activities and increased concentrations of lipid peroxides in plasma and tissue have been found in both patients and experimental animals with acute pancreatitis. The individual contribution of possible sources of free radicals (e.g., invading inflammatory cells, xanthine oxidase, cytochromes P450, nitric oxide synthase) is not yet clear, however. Since prophylactic administration of antioxidants diminished, in particular, pancreatic edema formation, free radicals seem to play an important role in the genesis of edema in acute pancreatitis. An involvement of free radicals in the pathogenesis of pancreatic necrosis could not yet be proven. Thus, no antioxidant treatment has proven useful for therapy of fulminant pancreatitis in animals to date. However, in severe acute pancreatitis characterized by death occurring after 12-18 hours, the seleno-organic compound Ebselen, which has a glutathione peroxidase-like activity, and the membrane permeable ascorbic acid derivative CV-3611 have been demonstrated to be effective. To date, controlled clinical studies have failed to demonstrate the therapeutic efficacy of antioxidant selenium or glutathione precursor supplementation. Therefore, further controlled clinical trials are needed to determine whether supplements of antioxidants can alter the clinical course of acute pancreatitis. Since the nitric oxide radical may even protect the pancreas, a purely negative discussion of the role of free radicals on the pancreas is not justified. The actual role of free radicals in acute pancreatitis, i.e. serving the body's defense against infection, being an epiphenomenon of the inflammatory process without pathophysiological relevance, or having true pathogenic significance, is not yet clear. Lipid peroxidation may perhaps not be the cause but rather the sequel of pancreatic inflammation and may likely reflect the severity of the systemic inflammatory response rather than that of pancreatic parenchyma damage. In vitro, exposure of isolated pancreatic acinar cells to oxidative stress caused rapid cell damage and death. Such knowledge from cellular studies might help to plan therapeutical trials to evaluate potentially effective therapies in the experimental animal, as well as in patients suffering from pancreatitis. Thus, to further clarify the role of oxidative stress in acute pancreatitis, an integrated approach is needed, including investigations at various biological levels, from isolated cells or even organelles to laboratory animals and, finally, clinical studies in man.

The role of calcium in pancreatitis.

BACKGROUND/AIMS: A large, sustained increase in acinar [Ca2+]i may play a key role in the pathogenesis of acute pancreatitis. Many mechanisms which lead to cell damage in vitro and pancreatitis in vivo, such as free radicals or supraphysiological cerulein concentrations, cause a rapid increase in [Ca2+]i in pancreatic acinar cells. Little is known about why [Ca2+]i increases in some instances stimulate secretion and in other instances initiate cell death. So far, [Ca2+]i increases were thought to represent physiological signals when they occurred as oscillations at the single cell level. METHODOLOGY: This paper reviews recent literature and our own original research about the role of calcium in the function of pancreatic acinar cells and the development of pancreatitis. RESULTS: Recent studies showed that exposure of acinar cells to free radicals not only caused a bulk increase in [Ca2+]i but also resulted in calcium oscillations which had a lower frequency than, but similar amplitude to oscillations occurring after physiological stimuli. The absolute increase in [Ca2+]i did not definitely determine the cellular response. Instead, the duration of [Ca2+]i increase may have been more important. In contrast to previous belief of a direct relationship between [Ca2+]i oscillations and exocytosis, recent results show that radicals can induce [Ca2+]i oscillations which do not exert exocytosis but inhibit the secretory response to physiological stimuli. Further experiments showed that the [Ca2+]i release caused by radicals originates from thapsigargin-insensitive, ryanodine-sensitive stores. CONCLUSIONS: The origin and duration of [Ca2+]i increases rather than their extent or oscillatory nature, determine whether the cell will secrete or die. An abnormal [Ca2+]i increase can trigger trypsin activation, acinar cell damage and acute pancreatitis. This hypothesis is supported by studies which show that calcium chelators inhibit radical-induced trypsin activation as well as cell necrosis and apoptosis. Thus, an inhibition of pathological [Ca2+]i release may have a therapeutic potential.

Supraphysiologic concentrations of cerulein induce apoptosis in the rat pancreatic acinar cell line AR4-2J.

Little is known as yet about the role of apoptosis in pancreatic damage. This study evaluated the effects of supraphysiologic concentrations of the cholecystokinin (CCK) analog, cerulein, which causes cell damage in vitro and acute pancreatitis in vivo, on cell proliferation and DNA fragmentation in the rat pancreatic acinar cell line AR4-2J. Cerulein inhibited the cell proliferation of AR4-2J time- and dose-dependently to approximately 60% of the control level at 10(-6) M after 72 h. DNA fragmentation, as assessed by both electrophoresis and enzyme-linked immunosorbent assay (ELISA), occurred at cerulein concentrations > or = 10(-8) M. The maximal DNA fragmentation as measured by ELISA was reached after 24 h. Cerulein at concentrations > or = 10(-9) M induced wild-type p53. Glutathione (1 mM) diminished the effects of cerulein on both cell proliferation and DNA fragmentation, whereas spermine (100 microM), which partially attenuated DNA fragmentation, did not have an effect on cell proliferation. The CCK-A-receptor antagonist loxiglumide completely abolished the effect of cerulein on DNA fragmentation. The serine-protease inhibitor FUT-175 (10 microM), the cysteine-protease inhibitor NCO-700 (5 mM), and ethylene glycol tetraacetic acid (EGTA; 500 microM) all had no effects on the changes in cell proliferation and DNA fragmentation induced by cerulein. The data suggest that supraphysiologic concentrations of cerulein rapidly induce apoptosis in AR4-2J cells and only later inhibit cell proliferation. These effects are mediated by CCK-A receptors. Cerulein-induced apoptosis may involve the induction of wild-type p53 or glutathione depletion or both.

Premature trypsinogen activation during cerulein pancreatitis in rats occurs inside pancreatic acinar cells.

Although it is widely accepted that trypsinogen activation is an initiating event in the development of acute pancreatitis, its location inside the pancreas is not known. In our studies, acute edematous pancreatitis was induced in rats by one or two intraperitoneal injections of 50 microg cerulein/kg body weight. The pancreas was removed for examination 1 or 2 h after the first and the second cerulein injection, respectively. The cleavage product of trypsinogen activation, trypsinogen activation peptide, was specifically labeled on pancreatic tissue sections by a corresponding antibody, the signal enhanced by a biotin-avidin conjugate, and the site then visualized by coupled peroxidase activity on diaminobenzidine. The sections were examined by light microscopy. Trypsinogen activation peptide, reflecting activation of the pancreatic digestive enzyme trypsinogen, was detected inside pancreatic acinar cells in this animal model of acute pancreatitis. As early as 1 h after the first injection of cerulein, protease activation was seen within the apical pole of acinar cells. Protease activation was increased 2 h after the latter of two injections of cerulein and more evenly distributed within the cells. For the first time morphologic evidence confirms that the activation originates within the acinar cell, rather than from the interstitium or the duct lumen. The location of this activation at the apical site of the acinar cell indicates its origin from subcellular compartments involving the late steps in the secretory pathway.

Inhibition of cathepsin B does not affect the intracellular activation of trypsinogen by cerulein hyperstimulation in isolated rat pancreatic acinar cells.

Activation of trypsinogen is thought to trigger the autodigestive process in acute pancreatitis. The lysosomal enzyme cathepsin B was suggested to cause the activation of trypsinogen because it is known that cathepsin B is able to activate trypsinogen in special circumstances and that lysosomal and digestive enzymes are colocalized within intracellular vacuoles in the early stage of pancreatitis. As yet this hypothesis has been difficult to prove because activated trypsin is difficult to quantify in pancreatitis by conventional enzymatic measurements. We therefore employed an ELISA for trypsin activating peptide (TAP), which is a small peptide cleaved during the activation of trypsinogen and can be determined reliably. Supraphysiological concentrations of cerulein (1 nM-1 microM) resulted in a marked increase in TAP in freshly isolated pancreatic acinar cells, indicating activation of trypsinogen. This activation as determined by the TAP increase was significantly reduced by the serine protease inhibitor Fut-175 but not by the cathepsin B inhibitors E-64 and NCO-700. The concentrations of NCO-700 and E-64 abolished the cathepsin B activity of pancreatic acinar cells but did not significantly reduce the trypsin activity (after enterokinase preincubation); correspondingly the concentrations of Fut-175 used abolished the trypsin activity but did not reduce the cathepsin B activity. The results indicate that an autoactivation of trypsin rather than an activation of trypsinogen by cathepsin B triggers trypsin activation by supramaximal cerulein concentrations.

Trypsinogen activation and glutathione content are linked to pancreatic injury in models of biliary acute pancreatitis.

CONCLUSION: In models of biliary acute pancreatitis, which might resemble the situation in humans, premature activation of trypsinogen inside the pancreas ("autodigestion") occurs and is correlated with the extent of ductal and parenchymal injury. It is accompanied by a critical spending of protease inhibitors and glutathione, compromising important acinar cell defense and maintenance mechanisms. BACKGROUND: Premature activation of pancreatic digestive enzymes and profound changes of levels of certain biochemical compounds have been implicated in the pathophysiology of acute pancreatitis. Hitherto, little information on their role in biliary acute pancreatitis has been available. METHODS: Three types of injury to the pancreaticobiliary duct system of various severity were induced in rats--ligation of the common bile-pancreatic duct, retrograde infusion of electrolyte, or retrograde infusion of taurocholate solution--and were compared to sham-operated animals. Trypsin, trypsin inhibitory capacity (TIC), reduced glutathione (GSH), and other compounds were measured in pancreatic tissue. Histopathology, as well as serum amylase, lipase, and gamma-glutamyl transferase (gamma GT) were assessed. RESULTS: Histopathology and elevated activity of gamma GT in the serum revealed increasing severity of pancreatic injury from sham operation through retrograde duct infusion with taurocholate. GSH was diminished even in macroscopically normal-appearing tissue, but significantly lower in altered (hemorrhagic)-looking sections. Conversely, tissue levels of trypsin were significantly increased. TIC was elevated only in the duct obstruction model, whereas it was reduced in the retrograde duct infusion models.

Cell volume changes modulate cholecystokinin- and carbachol-stimulated amylase release in isolated rat pancreatic acini.

BACKGROUND & AIMS: Changes in cell volume have been recently identified as modulators of cell function and gene expression. This study evaluated the regulation of exocrine secretion by pancreatic acini on the basis of changes in cell hydration. METHODS: Acini were exposed to hypotonicity or hypertonicity. The effects of corresponding changes in cell volume on various cell functions were analyzed. RESULTS: Hypertonicity and hypotonicity caused a stepwise cell shrinkage and swelling, respectively. Cell shrinkage decreased and cell swelling increased amylase secretion stimulated by cholecystokinin (CCK) and carbachol but not by secretin. Changes in cell volume did not alter basal or CCK-stimulated calcium concentrations or CCK-stimulated inositol triphosphate generation. The regulation of secretion by cell volume is not mediated via changes in CCK receptor binding or protein kinase C. The increase of amylase release caused by hypotonicity was completely inhibited by cytochalasin B, colchicine, and genistein. Hypotonicity as well as CCK caused activation of mitogen-activated protein kinases. CONCLUSIONS: Changes in cell volume regulate exocrine secretion of pancreatic acini. The effects were found only for secretagogues that act via the calcium/inositol-trisphosphate pathway. However, the mechanisms involved are located at luminal parts of the signal-transduction cascade and involve the cytoskeleton, protein phosphorylation, and activation of mitogen-activated protein kinases.

Beneficial effects of L-2-oxothiazolidine-4-carboxylate on cerulein pancreatitis in mice.

BACKGROUND & AIMS: Disturbances of the thiol metabolism of acinar cells may play a role in the pathophysiology of acute pancreatitis. Cerulein-induced pancreatitis causes depletion of glutathione. The entire pancreatic thiol status was assessed in this model. The potential benefit of augmentation of pancreatic glutathione by L-2-oxothiazolidine-4-carboxylate (OTC) for the course of pancreatitis was determined. METHODS: Mice were treated with cerulein (50 microg/kg) and with or without administration of OTC (6.5 and 20 mmol/kg, respectively). Pancreatic tissue was analyzed for reduced and oxidized glutathione, nonprotein thiol, mixed disulfide, protein thiol, and protein disulfide. Histopathology and serum amylase were also assessed. RESULTS: Levels of all thiol compounds were altered profoundly at a different rate during pancreatitis. OTC caused an increase of 60% in pancreatic glutathione. Its administration at 20 mmol/kg attenuated the decrease of pancreatic glutathione and protein thiol until 8 hours and blunted the cerulein-induced increase in amylase activity and histopathologic damage. At 6.5 mmol/kg, OTC failed to show effects on all parameters. CONCLUSIONS: OTC administered in a prophylactic protocol dose-dependently exerted beneficial effects in cerulein-induced pancreatitis in mice despite only transient influence on pancreatic thiol compounds. Thiols (e.g., reduced glutathione) and their corresponding disulfides are critically involved in the pathophysiology of cerulein-induced pancreatitis.