[Acute hemorrhage in the upper gastrointestinal tract]. / Akute Blutung im oberen Gastrointestinaltrakt.

Bleeding in the upper gastrointestinal (GI) tract is a frequent and complex emergency. There are guidelines for acute medical treatment, established endoscopic treatment as well as surgical and radiological rescue procedures. Nevertheless, the mortality of the upper GI tract bleeding is high, which is due to the fact that affected patients often have serious preexisting illnesses.

Very low rates of Helicobacter pylori infection in organ transplant recipients presenting with peptic ulcer disease.

BACKGROUND: Leading causative factors of peptic ulcer disease (PUD) in the general population are infection with Helicobacter pylori (HP) and exposure to non-steroidal anti-inflammatory drugs (NSAID). We hypothesized that this may be different in transplant recipients given increased exposure of immunosuppressive and anti-microbial drugs. METHODS: We performed a retrospective single center analysis of all patients presenting with PUD to the endoscopy unit at a tertiary care and transplant center in Germany between 2006 and 2013. PUD was diagnosed by upper endoscopy. HP was identified by biopsy and histology. Organ transplant recipients were compared to non-transplant recipients (control group). RESULTS: 66 patients with PUD were identified in the study period. 12% (44/366) had previously received an organ transplant. 7% (3/44) of transplant recipients were found to be positive for HP compared to 25% (81/322) in the control group (p=0.007). Even when excluding patients taking proton-pump-inhibitors (PPI) from the analysis rates were similar with 30% (65/214) of the ulcers being HP positive in the control group compared to 14% (1/7) in transplant recipients (p=0.006). Furthermore, in the transplant recipient group rates of being in intensive care, concurrent PPI and concurrent antibiotic medication were significantly higher than in the control group. CONCLUSION: Organ transplant recipients with PUD have lower rates of Helicobacter pylori positivity compared to the general population.

Evaluation of Liver and Spleen Stiffness with Acoustic Radiation Force Impulse Quantification Elastography for Diagnosing Clinically Significant Portal Hypertension.

PURPOSE: Hepatic vein pressure gradient (HVPG) is the gold standard for diagnosing clinically significant portal hypertension (CSPH). The aim of this study was to investigate-in comparison to HVPG-the ability to diagnose CSPH by liver and spleen stiffness measurements obtained by acoustic radiation force impulse (ARFI) imaging. MATERIALS AND METHODS: A total of 78 patients (mean age: 53 ±â€Š13 years, 62 % male) with chronic liver disease were enrolled in this study. Each patient received liver (LSM) and spleen (SSM) stiffness measurements by ARFI, an HVPG measurement and a transjugular liver biopsy on the same day. Patients were classified according to their HVPG into three different groups: HVPG < 10 mmHg, HVPG ≥ 10-< 12 mmHg and HVPG ≥ 12 mmHg. RESULTS: LSM, SSM were significantly higher in patients with HVPG ≥ 10 - < 12 in comparison to HVPG < 10 mmHg (p < 0.001 and p < 0.001, respectively), and in patients with HVPG ≥ 12 mmHg in comparison to ≥ 10 - < 12 mmHg (p < 0.001 and p < 0.001, respectively). LSM and SSM were able to diagnose HVPG ≥ 10 mmHg and HVPG ≥ 12 mmHg with high diagnostic performance (AUC LSM: 0.93 and 0.87, respectively; AUC SSM: 0.97 and 0.95, respectively). The AUC of SSM in predicting esophageal varices (EVs) plus HVPG ≥ 10 mmHg and EVs plus HVPG ≥ 12 mmHg were higher compared to LSM in both groups of patients (SSM: 0.90 and 0.93 vs. LSM: 0.84 and 0.88, respectively). No significant difference between both AUCs was detected in the different HVPG groups. In the multivariate -analysis SSM remained a factor predicting HVPG (HVPG > 10 mmHg p = 0.007; HVPG ≥ 12 mmHg p = 0.003). CONCLUSION: LSM and SSM by ARFI are noninvasive diagnostic tools that may help in diagnosing CSPH. LSM and SSM could be used as a guiding noninvasive screening tool in patients with esophageal varices requiring endoscopic evaluation.

[Improvement of cost allocation in gastroenterology by introduction of a novel service catalogue covering the complete spectrum of endoscopic procedures]. / Verbesserung der Kostenkalkulation in der Gastroenterologie durch Einführung eines neuen Leistungskatalogs für alle endoskopischen Prozeduren.

BACKGROUND: The German hospital reimbursement system (G-DRG) is incomplete for endoscopic interventions and fails to differentiate between complex and simple procedures. This is caused by outdated methods of personnel-cost allocation. METHODS: To establish an up-to-date service catalogue 50 hospitals made their anonymized expense-budget data available to the German-Society-of-Gastroenterology (DGVS). 2.499.900 patient-datasets (2011-2013) were used to classify operation-and-procedure codes (OPS) into procedure-tiers (e.g. colonoscopy with biopsy/colonoscopy with stent-insertion). An expert panel ranked these tiers according to complexity and assigned estimates of physician time. From June to November 2014 exact time tracking data for a total 38.288 individual procedures were collected in 119 hospitals to validate this service catalogue. RESULTS: In this three-step process a catalogue of 97 procedure-tiers was established that covers 99% of endoscopic interventions performed in German hospitals and assigned validated mean personnel-costs using gastroscopy as standard. Previously, diagnostic colonoscopy had a relative personnel-cost value of 1.13 (compared to gastroscopy 1.0) and rose to 2.16, whereas diagnostic ERCP increased from 1.7 to 3.62, more appropriately reflecting complexity. Complex procedures previously not catalogued were now included (e.g. gastric endoscopic submucosal dissection: 16.74). DISCUSSION: This novel service catalogue for GI-endoscopy almost completely covers all endoscopic procedures performed in German hospitals and assigns relative personnel-cost values based on actual physician time logs. It is to be included in the national coding recommendation and should replace all prior inventories for cost distribution. The catalogue will contribute to a more objective cost allocation and hospital reimbursement - at least until time tracking for endoscopy becomes mandatory.

Clinical value and safety of liver biopsies in patients transplanted for hepatitis C virus-related end-stage liver disease.

BACKGROUND: Hepatitis C is the leading indication for liver transplantation. Differentiation between recurrent graft hepatitis C (RGH-C) and graft rejection (GR) is challenging. Liver biopsy is standard to diagnose both conditions; however, little information is available regarding this procedure in hepatitis C virus (HCV)-infected liver transplant recipients. METHODS: Liver biopsies (n = 211) from all consecutive patients (n = 138) transplanted for hepatitis C at Hannover Medical School between January 2000 and October 2011 were screened, and a final cohort of 96 patients with 196 biopsies was included. Indications, histopathological findings, and biopsy-related complications were documented. Modifications in the treatment based on the biopsy result and the biochemical outcome were analyzed. RESULTS: Most biopsies (196/211, 93%) were representative. Five patients (2.5%) developed non-fatal biopsy-related complications. Biopsy results were GR (35%), RGH-C (31%), and other diagnoses (34%). GR was independently associated with lower albumin (P = 0.025) and higher bilirubin levels (P = 0.011). Treatment was modified based on the biopsy result in 25% of cases. Alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), and bilirubin levels improved in 41%, 25%, and 31% of cases 4 weeks post biopsy respectively. ALT improvements were more significant in patients with GR than in those with RGH-C. CONCLUSION: Liver biopsy in HCV-infected liver transplant recipients is safe and representative in >90% of cases. GR is independently associated with lower albumin and higher bilirubin levels.

Endoscopic closure of esophageal intrathoracic leaks: stent versus endoscopic vacuum-assisted closure, a retrospective analysis.

BACKGROUND AND STUDY AIM: Placement of covered self-expanding metal or plastic stents (SEMS or SEPS) is an established method for managing intrathoracic leaks. Recently, endoscopic vacuum-assisted closure (EVAC) has been described as a new effective treatment option. Our aim was to compare stent placement with EVAC for nonsurgical closure of intrathoracic anastomotic leaks. PATIENTS AND METHODS: In a retrospective analysis we were able to identify 39 patients who were treated with SEMS or SEPS and 32 patients who were treated with EVAC for intrathoracic leakage. In addition to successful fistula closure, we analyzed hospital mortality, number of endoscopic interventions, incidence of stenoses, and duration of hospitalization. RESULTS: In a multivariate analysis, successful wound closure was independently associated with EVAC therapy (hazard ratio 2.997, 95 % confidence interval [95 %CI] 1.568 - 5.729; P = 0.001). The overall closure rate was significantly higher in the EVAC group (84.4 %) compared with the SEMS/SEPS group (53.8 %). No difference was found for hospitalization and hospital mortality. We found significantly more strictures in the stent group (28.2 % vs. 9.4 % with EVAC, P < 0,05). CONCLUSIONS: EVAC is an effective endoscopic treatment option for intrathoracic leaks and showed higher effectiveness than stent placement in our cohort.

[Secondary sclerosing cholangitis following liver transplantation: a rare cause for graft failure]. / Sekundär sklerosierende Cholangitis nach Lebertransplantation: Eine seltene Ursache für ein Transplantatversagen.

We report on a 25-year-old female patient who presented with recurrent cholestasis following liver transplantation due to primary sclerosing cholangitis. Abdominal ultrasound and computed tomography showed intrahepatic bile duct dilatation and stenosis of the common hepatic artery with flow acceleration and decreased resistance index. The patient developed a severe secondary sclerosing cholangitis (SSC) with biliary casts - despite interventional stent placement of the common hepatic artery - thus requiring retransplantation. After prolonged intensive care unit treatment the patient was discharged in a good general condition. This case report describes SSC as a rare cause for graft failure. In unclear cholestasis after liver transplantation SSC has to be considered as the underlying cause.

[Endoscopic vacuum-assisted closure]. / Endoskopische Vakuumschwammtherapie.

Anastomotic leakage in the upper and lower intestinal tract is associated with high morbidity and mortality. Within the last 10 years endoscopic treatment options have been accepted as sufficient treatment option of these surgical complications. Endoscopic vacuum assisted closure (E-VAC) is a new innovative endoscopic therapeutic option in this field. E-VAC transfers the positive effects of vacuum assisted closure (VAC) on infected cutaneous wounds to infected cavities that can only be reached endoscopically. A sponge connected to a drainage tube is endoscopically placed in the leakage and a continuous vacuum is applied. Sponge and vacuum allow removal of infected fluids and promote granulation of the leakage. This results in clean wound grounds and finally allows wound closure. Meanwhile the method was also successfully used in the treatment of necrotic pancreatitis.

Secondary sclerosing cholangitis in critically ill patients: model of end-stage liver disease score and renal function predict outcome.

Secondary sclerosing cholangitis in critically ill patients (SSC - CIP) is an underdiagnosed emerging disease. The aim of this study was to characterize clinical features and prognostic factors for mortality in SSC - CIP. This retrospective study included 54 patients who were diagnosed via endoscopic retrograde cholangiopancreatography (ERCP) after cardiothoracic surgery (n = 21), sepsis (n = 13), polytrauma (n = 11), and others (n = 9). In total, 33 patients who either died (n = 27) or needed liver transplantation (n = 6) were compared with surviving patients (n = 21). The model for end-stage liver disease (MELD) score and need for renal replacement therapy were independent risk factors for mortality. Compared with ERCP, accuracy was 30% for ultrasound and 36 % for liver biopsies. As a result of microbiological bile analysis, 28 % of patients required a change in antibiotic treatment. SSC - CIP is frequently a fatal disease. ERCP should be considered in selected patients to establish the diagnosis and hence provide useful clinical information.

Measurement of IgG4 in bile: a new approach for the diagnosis of IgG4-associated cholangiopathy.

BACKGROUND AND STUDY AIMS: Immunoglobulin G4 (IgG4)-associated cholangitis (IAC) is difficult to diagnose because on cholangiography the associated biliary tract strictures cannot be differentiated from cholangiocarcinoma or primary sclerosing cholangitis (PSC). Serum IgG4 levels show a low sensitivity and specificity and are unreliable, particularly in patients with related diseases such as PSC. As IAC takes place at the biliary epithelium, we hypothesized that IgG4 measurement in bile may have higher sensitivity compared with serum. METHODS: Bile and serum samples were collected during cholangiography in 67 patients, including 23 patients with PSC, 25 with cholangiocarcinoma, 14 with choledocholithiasis, and five with IAC. IgG4 was measured in both bile and serum. RESULTS: Bile IgG4 levels were markedly elevated in patients with IAC compared with patients with other biliary disorders. Whereas elevated serum IgG4 levels were found both in patients with PSC and IAC, biliary IgG4 levels were only increased in patients with IAC. CONCLUSIONS: The study demonstrates that bile IgG4 measurement is possible and may help to distinguish IAC from other diseases.

[Biliary diseases - new insights and developments]. / Gallenwegserkrankungen - neue Erkenntnisse und Entwicklungen.

This article focuses on the new insights and developments in biliary tract disorders. In patients with large bile duct stones, balloon dilation after the after endoscopic sphincterotomy appears to be an effective alternative to mechanical lithotripsy. A 2-month biliary stenting reduces stone size and number of stones. Early laparoscopic cholecystectomy in patients with cholezysto- and choledocholithiasis appears to be safe and might prevent biliary complications in the period following sphincterotomy. A bile sample collected during cholangiography for microbiological analysis is a simple, potentially valuable, diagnostic tool in patients with cholangitis. Each center should recognize its own patterns of infection to ensure ideal targeted therapy. In patients with primary biliary cirrhosis (PBC), development of fatigue is an independent risk factor of increased mortality. The risk of osteoporosis is increased in women with PBC and their risk of fracture increased significantly already at a T-score lower than -1.5. For PBC-patients not responding on UDCA-therapy, fenofibrate may be a new therapeutic approach. The incidence of primary sclerosing cholangitis (PSC) increases significantly in Scandinavia. In PSC patients with dominant stenosis the additional presence of inflammatory bowel disease is associated with an increased risk of cancer and a decreased survival. The risk of osteoporosis in PSC patients is significantly increased, especially in those with long-standing inflammatory bowel disease. In patients with advanced cholangiocarcinoma, bilateral stenting of the bile ducts is associated with better prognosis. The combination therapy with gemcitabine and cisplatin is an appropriate option for the treatment of patients with advanced biliary cancer.

[Autoimmune polyglandular syndromes]. / Autoimmun polyglanduläre Syndrome.

Autoimmune polyglandular syndromes are rare autoimmune endocrinopathies, which can be also associated with non endocrine autoimmune diseases. The autoimmune polyglandular syndrome type I (autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy; APECED) is distinguished from autoimmune polyglandular syndrome type 2 (APS-2). Main symptoms of APECED are adrenal insufficiency, hypoparathyroidism and candidiasis. The diagnosis is established when two out of three of these symptoms are present. APECED is associated with mutations of the autoimmune regulator gene (AIRE) and predominantly affects juvenile patients with a family background from Sardinia, Finland and Iranian Jews. The APS-2 is not AIRE associated. It is characterized by the presence of autoimmune thyroid disease, adrenal insufficiency and/or diabetes mellitus type I. APS-2 is more common than APECED and mainly affects adult women without any preference of a certain ethnic group. Therapy consists of hormone replacement therapy and treatment of clinical symptoms. In some APECED patients immunosuppressive therapy seems to be promising.

A possible role for Ca(2+)/calmodulin-dependent protein kinase IV during pancreatic acinar stimulus-secretion coupling.

Ca(2+)/calmodulin-dependent protein kinases (CaMKs) are important intracellular mediators in the mediation of stimulus-secretion coupling and excitation-contraction coupling in a wide variety of cell types. We attempted to identify and characterize the functional roles of CaMK in mediating pancreatic enzyme secretion. Immunoprecipitation and immunoblotting studies using a CaMKII or CaMKIV antibody showed that rat pancreatic acini expressed both CaMKII and CaMKIV. Phosphotransferase activities of CaMKs were measured by a radioenzyme assay (REA) using autocamtide II, peptide gamma and myosin P-light chain as substrates. Although CaMKII and CaMKIV use autocamtide II as a substrate, peptide gamma is more efficiently phosphorylated by CaMKIV than by CaMKII. Intact acini were stimulated with cholecystokinin (CCK)-8, carbachol (CCh) and the high-affinity CCK-A receptor agonist, CCK-OPE, and the cell lysates were used for REA. CCK-8, CCh and CCK-OPE caused a concentration-dependent increase in CaMKs activities. When autocamtide II was used, maximal increases were 1.5-1.8-fold over basal (20.2+/-2.0 pmol/min/mg protein), with peaks occurring at 20 min after cell stimulation. In separate studies that used peptide gamma, CCK-8, CCh and CCK-OPE dose-dependently increased CaMKIV activities. Maximal increases were 1.5-2.4-fold over basal (30.7+/-3. 2 pmol/min/mg protein) with peaks occurring at 20 min after cell stimulation. Peak increases after cell stimulation induced by peptide gamma were 1.8-2.8-fold higher than those induced by autocamtide II. CCK-8, CCh and CCK-OPE also significantly increased phosphotransferase activities of myosin light chain kinase (MLCK) substrate (basal: 4.4+/-0.7 pmol/min/mg protein). However, maximal increases induced by MLCK substrate were less than 10% of those occurring in peptide gamma. Characteristics of the phosphotransferase activity were also different between autocamtide II and peptide gamma. When autocamtide II was used, elimination of medium Ca(2+) in either cell lysates or intact cells resulted in a significant decrease in the activity, whereas it had no or little effect when peptide gamma was used. This suggests that Ca(2+) influx from the extracellular space is not fully required for CaMKIV activity and Ca(2+) is not a prerequisite for phosphotransferase activity once CaMKIV is activated by either intracellular Ca(2+) release or intracellular Ca(2+) oscillations. The specific CaMKII inhibitor KN-62 (50 microM) had no effect on the CaMKIV activity and pancreatic enzyme secretion elicited by CCK-8, CCh and CCK-OPE. The specific MLCK inhibitor, ML-9 (10 microM), also did not inhibit CCK-8-stimulated pancreatic amylase secretion. In contrast, wide spectrum CaMK inhibitors, K-252a (1 microM) and KT5926 (3 microM), significantly inhibited CaMKIV activities and enzyme secretion evoked by secretagogues. Thus, CaMKIV appears to be an important intracellular mediator during stimulus-secretion coupling of rat pancreatic acinar cells.

High-affinity cholecystokinin type A receptor/cytosolic phospholipase A2 pathways mediate Ca2+ oscillations via a positive feedback regulation by calmodulin kinase in pancreatic acini.

In rat pancreatic acini, we previously demonstrated that depending on the agonist used, activation of cholecystokinin type A (CCKA) receptor (CCK-AR) results in the differential involvement of the cytosolic phospholipase A2 (cPLA2), phospholipase Cbeta1 (PLCbeta1) and Src/protein tyrosine kinase (PTK) pathways. The high-affinity CCK-AR appears to be coupled to the Gbeta/cPLA2/arachidonic acid (AA) cascade in mediating Ca2+ oscillations. The low-affinity CCK-AR is coupled to both the Galphaq/11/PLCbeta1/inositol 1,4,5-trisphosphate (IP3) to evoke intracellular Ca2+ release and the Src/PTK pathway to mediate extracellular Ca2+ influx. The objectives of this study were to provide evidence that cPLA2 is present in pancreatic acini and to evaluate the possibility that its activation results in Ca2+ oscillations and amylase secretion. Furthermore, we investigated the mechanism of Ca2+ oscillations mediated by the high-affinity CCK-AR. In rat pancreatic acini, immunoprecipitation studies using an anti-cPLA2 monoclonal antibody, demonstrated a cPLA2 band at the location of 110 kDa. A selective inhibitor of cPLA2, AACOCF3 (100 microM), inhibited production of AA metabolites, Ca2+ oscillations and amylase secretion elicited by the high-affinity CCK-AR agonist, CCK-OPE (10-1000 nM). In addition, through the repetitive release of intracellular Ca2+, CCK-OPE enhanced phosphotransferase activities of Ca2+/calmodulin-dependent protein kinase type IV (CaMK IV), which were inhibited by AACOCF3. The CaMK inhibitor, K252-a (1-3 microM), also abolished basal and CCK-OPE-stimulated CaMK IV activities. The CaM inhibitor, W-7 (100 microM), and K252-a inhibited Ca2+ oscillations and amylase secretion evoked by CCK-OPE without affecting the AA formation. Therefore, it appears that Ca2+ oscillations elicited by the high-affinity CCK-AR/Gbeta/cPLA2/AA pathway activate CaMK IV. Activated CaMK, in turn, regulates Ca2+ oscillations through a positive feedback mechanism to mediate pancreatic exocytosis.