ZusammenfassungDie Mehrzahl der Gallenwegsverletzungen ereignet sich im Rahmen operativer Eingriffe. Als Folge können sich Gallenfisteln in die freie Bauchhöhle, den Magen-Darm-Trakt und das Bronchialsystem oder Strikturen der Gallenwege entwickeln. Bei daraus entstehenden chronischen Cholangitiden und Cholestasen ist die Entwicklung einer biliären Leberzirrhose möglich. Eine Besonderheit stellen sekundäre Schäden des Gallenwegssystems bei schwerem Schock dar. Hierzu zählen die Gallenblasennekrose („Schockgallenblase“) und posttraumatisch sekundär sklerosierende Cholangitis. Verletzungen der Leber können akut zu lebensbedrohlichen Blutungen und Schockzuständen führen. Die Bestimmung von GdB/GdS/MdE orientiert sich an sekundären Funktionsstörungen. Wegen der guten Regenerationsfähigkeit des Leberparenchyms sind anhaltende Störungen der Organfunktion nach Lebertrauma die Ausnahme.

Abdominelle Traumen durch stumpfe oder penetrierende Verletzungen können zu Organperforation (Magen, Duodenum, Jejunum, Ileum, Kolon) und/oder Blutungen mit der Notwendigkeit der zeitnahen chirurgischen Intervention führen. Bei Ingestion starker Säuren oder Laugen stehen Verletzungen des Ösophagus im Vordergrund; Nekrosen bis hin zur Perforation des Magens sind jedoch möglich. Verletzungen des Pankreas sind in der Mehrzahl penetrierender Natur und die Schwere durch das Ausmaß Gangrupturen bestimmt. Der Grad der Schädigung orientiert sich am dauerhaften Funktionsverlust (Kurzdarmsyndrom, Anus praeter, Stenosen, endokrine/exokrine Pankreasinsuffizienz).

Background: /Objectives: Sequence variants in several genes have been identified as being associated with an increased inherited risk to develop chronic pancreatitis (CP). In a genetic survey of a CP patient we identified in the PRSS1gene a new c.380C > G sequence variation, giving rise to a non-synonymous p.S127C mutation. Functional studies were performed to analyze the associated pathophysiology of the variant. Methods: Following generation of an expression vector for the new PRSS1 variant we compared its expression, secretion and catalytic activity with already known PRSS1 risk variants in HEK 293T cells. The intracellular protein accumulation and induction of endoplasmic reticulum (ER)-stress was analyzed. Results: Prediction tool analysis indicated a probably deleterious effect of the p.S127C variant on protein function which was confirmed by detection of a secretion defect in HEK293T cells leading to intracellular protein accumulation. While protein misfolding was associated with reduced trypsin activity, the increased expression of BIP and presence of spliced XBP1 indicated that the p.S127C variant induces ER stress and activates the UPR signaling pathway. Conclusions: The disease mechanism of the PRSS1 p.S127C variant involves defective protein secretion and the induction of ER-stress due to accumulation of presumably misfolded trypsinogen within the ER. The new variant should be considered disease-causing with an incomplete penetrance. Our results confirm that in addition to dysregulated trypsin-activity or reduced fluid secretion, ER-stress induction is an important trigger for acinar cell damage and the development of recurrent or chronic pancreatic inflammation. (C) 2022 The Authors. Published by Elsevier B.V

Virusinfektionen der Leber stellen häufige Ursachen akuter und chronischer Leberentzündungen dar. Das Hepatitis A- und E-Virus verursachen in der Regel akute selbstlimitierende Erkrankungen; gleiches gilt für Begleithepatitiden im Rahmen nicht klassisch hepatotroper Virusinfektionen durch z. B. Cytomegalie-, Epstein-Barr- oder Masern-Virus. Die in den entwickelten Ländern autochthon vorkommende Hepatitis E kann sich durch extrahepatisch-neurologische Krankheitsbilder manifestieren. Die Hepatitis B, D oder C können in eine chronische Verlaufsform übergehen. Die chronische Hepatitis B ist gut behandelbar, die Hepatitis C ist heilbar. Im Berufskrankheitswesen steht die eindeutige Diagnosestellung am Beginn des Feststellungsverfahrens. Die Anerkennung als Berufskrankheit (BK 3101) bedarf des Nachweises der Wahrscheinlichkeit, dass die Infektion im Rahmen der versicherten Tätigkeit erworben wurde; die Möglichkeit allein genügt nicht. Die schuldhafte Ansteckung einer anderen Person mit Hepatitis B/D oder C kann nach dem Strafgesetzbuch als Körperverletzung gewertet und bestraft werden (§ 223, 229 StGB).

Objective:To evaluate (1) the efficacy of transit bipartition (TB) as revisional bariatric surgery (RBS) after laparoscopic sleeve gastrectomy (LSG); (2) the impact of the length of the common channel (CC) on weight loss.Background:LSG in combination with TB has been shown to be highly efficacious for treating morbid obesity. The role of TB as RBS to address the problem of primary failure or weight recidivism after LSG is less well defined.Methods:Observational study of outcomes in 100 morbidly obese patients who received a TB following LSG. Follow-up examinations (FE) were performed at 1, 3, 6, and 12 months. Variables analyzed included BMI, percent excess weight loss (%EWL), total body weight loss (%TBWL), effect on obesity-related conditions and complications.Results:The mean BMI before LSG was 49.9 ± 8.5 kg/m2. A nadir of 32.7 ± 6.1 kg/m2 was reached 22.1 ± 16.9 months after LSG (%EWL 70.0 ± 14.5). The time interval between LSG and TB was 52.2 ± 26.6 months at which the BMI had increased to 37.6 ± 7.1 kg/m2 and %EWL decreased to 49.4 ± 19.7. Following TB, the BMI decreased continuously to 31.4 ± 5.7 kg/m2 after 12 months with a parallel increase in %EWL to 74.7 ± 20.3 and %TWL reaching 36.3 ± 10.5. Weight loss was significantly higher for CC length of 250 versus 300 cm after 12 months (BMI 29.4 ± 5.3/33 ± 5.3 kg/m2, P = 0.002; %EWL 79.8 ± 26.6/70.4 ± 17; P = 0.009). Improvement of comorbidities was observed in a high proportion of patients. Major early complications occurred in 3% of the patients.Conclusion:TB is an effective second-step procedure to address insufficient weight loss or weight recidivism after LSG. CC length of 250 versus 300 cm had a significant impact. While most improvements of obesity-related comorbidities are likely linked to weight loss, amelioration of GERD is largely mediated by accelerated gastric emptying. Major complications were observed in 3% of patients and managed without fatalities.

BACKGROUND:Chronic hepatitis C virus (HCV)-infection is a slowly debilitating and potentially fatal disease with a high estimated number of undiagnosed cases. Given the major advances in the treatment, detection of unreported infections is a consequential step for eliminating hepatitis C on a population basis. The prevalence of chronic hepatitis C is, however, low in most countries making mass screening neither cost effective nor practicable.METHODS:We used a Kohonen artificial neural network (ANN) to analyze socio-medical data of 1.8 million insurants for predictors of undiagnosed HCV infections. The data had to be anonymized due to ethical requirements. The network was trained with variables obtained from a subgroup of 2544 patients with confirmed hepatitis C-virus (HCV) infections excluding variables directly linked to the diagnosis of HCV. All analyses were performed using the data mining solution "RayQ". Training results were visualized three-dimensionally and the distributions and characteristics of the clusters were explored within the map.RESULTS:All 2544 patients with confirmed chronic HCV diagnoses were localized in a clearly defined cluster within the Kohonen self-organizing map. An additional 2217 patients who had not been diagnosed with hepatitis C co-localized to the same cluster, indicating socio-medical similarities and a potentially elevated risk of infection. Several factors including, age, diagnosis codes and drug prescriptions acted only in conjunction as predictors of an elevated HCV risk.CONCLUSIONS:This ANN approach may allow for a more efficient risk adapted HCV-screening. However, further validation of the prediction model is required.

Background: Spontaneous reports of acute liver injuries (ALI) in patients taking dronedarone triggered an EMA alert in 2011. This study aimed to assess the risk of ALI for class III antiarrhythmic drugs controlling for the use of other potential ALI-inducing drugs. Methods: Between 2010 and 2014, consecutive ALI cases (>= 50 years-old) were identified across Germany. ALI was defined as a new increase in at least one of the transaminases >= 3 times the upper limit of normal (ULN) or >= 2 ULN if alkaline phosphatase, with ("definite" case) orwithout ("biochemical" case) suggestive signs/ symptoms of ALI, excluding other liver diseases. Recruited community controls were matched to cases on gender, age and inclusion date. Exposure to antiarrhythmic drugs and co-medication up to 2 years before ALI onset was informed by patients and confirmed by physicians' prescriptions. Adjusted Odds Ratios (aOR) were obtained from conditional multivariable logistic regressions, adjusted for a multivariate disease risk score and co-medication. Results: 252 cases and 1081 matched controls were included (59.1% females; mean age: 64 years). Exposure to class III antiarrhythmic drugs was 4.0% in cases and 1.5% in controls, aOR= 3.6 (95% CI: 1.6-8.4). Associations with exposure to dronedarone and amiodarone were respectively 3.1 (95% CI: 0.7-14. 8) and 5.90 (1.7-20.0). Restricting the analysis to definite or severe ALI cases did not change these results. Conclusions: Class III antiarrhythmic drugswere associatedwith ALI, amiodarone displaying the highest risk, and results were robust to case definitions. Continued vigilance is needed for patients taking these drugs. (C) 2018 Published by Elsevier B.V.

Background. Antibiotic-associated diarrhea (AAD) and Clostridium difficile-associated diarrhea (CDAD) are common complications of antibiotic use. Data on the efficacy of probiotics to prevent AAD and CDAD are unclear. We aimed to evaluate the efficacy of Saccharomyces boulardii to prevent AAD and CDAD in hospitalized adult patients.Methods. We conducted a multicenter, phase III, double-masked, randomized, placebo-controlled trial in hospitalized patients who received systemic antibiotic treatment in 15 hospitals in Germany between July 2010 and October 2012. Participants received Perenterol forte 250 mg capsules or matching placebo twice per day within 24 hours of initiating antibiotic treatment, continued treatment for 7 days after antibiotic discontinuation, and were then observed for 6 weeks.Results. Two thousand four hundred forty-four patients were screened. The trial was stopped early for futility after inclusion of 477 participants. Two hundred forty-six patients aged 60.1 +/- 16.5 years and 231 patients aged 56.5 17.8 were randomized to the S boulardii group and the placebo group, respectively, with 21 and 19 AADs in the respective groups (P = .87). The hazard ratio of AAD in the S boulardii group compared with the placebo group was 1.02 (95% confidence interval,.55-1.90; P = .94). Clostridium difficile-associated diarrhea occurred in 0.8% of participants (4 of 477). Nine serious adverse events were recorded in the S boulardii group, and 3 serious adverse events were recorded in the placebo group. None were related to study participation.Conclusions. We found no evidence for an effect of S boulardii in preventing AAD or CDAD in a population of hospitalized patients without particular risk factors apart from systemic antibiotic treatment.

Die zunehmende Adipositasprävalenz ist ein weltweites Gesundheitsproblem. Konservative, medikamentöse und endoskopische Therapiestrategien sind dabei wenig erfolgreich und die bariatrische Chirurgie ist nur für einen kleinen Patientenkreis nutzbar.

The gallbladder is an uncommon site of metastatic cancer. Although ultrasound can be regarded as a first line investigation for the detection of gallbladder lesions, differentiation between benign and malignant tumors usually requires resection. Real-time contrast enhanced ultrasound (CEUS) is a well-established technique for the classification of liver, pancreatic, and renal diseases (Weskott, 2008). The application of CEUS in the diagnosis of gallbladder tumors has rarely been described. We report the application of contrast enhanced ultrasound for the characterization of a gallbladder lesion in a 63-year-old patient with a history of renal cell and rectal cancer.

Background Endoscopic polypectomy significantly reduces the incidence of colorectal cancer, but recurrence rates are high, especially for adenomas with advanced histology. The present guidelines recommend re-colonoscopy 3 to 5 years later. Due to limited resources, more precise predictions of adenoma recurrence are required. Design Lesions from 109 patients with colorectal adenomas recruited into a randomized, placebo-controlled chemoprevention trial with mesalazine were included. Formalin-fixed paraffin-embedded tissue sections were stained for ß-catenin, cyclooxygenase-2 (Cox-2), and p53 and scored. Adenoma recurrence rates were recorded after 3 years and associated with clinical and immunohistochemical parameters by contingency table analysis. Results After 3 years, adenomas recurred in 51.4 % of patients. Out of 109 adenomas, 95 met at least one criterion of advanced adenoma (size >1 cm, villous histology, high-grade intraepithelial neoplasia). There was no influence of age, sex, size or villous histology on adenoma reappearance, whilst the number of adenomas at baseline was positively associated with recurrence ( p = 0.003). In contrast, ß-catenin nuclear localisation, Cox-2 expression and p53 nuclear expression were significantly associated with adenoma recurrence after 3 years (ß-catenin: p = 0.002; Cox-2: p = 0.001; p53: p = 0.001). Combining these three markers led to a negative predictive value of 88.5 % and a sensitivity of 94.6 %. (OR = 13.54) Conclusions Scoring each single parameter and, more strongly, the combination of all three parameters of the expression of ß-catenin, Cox-2 and p53 in colorectal adenoma tissue may be a useful negative predictor for adenoma recurrence in patients with advanced colorectal adenomas.

Surveillance colonoscopy is an important strategy for prevention of colorectal cancer. 5-aminosalicylate (ASA) (mesalazine) is discussed as a chemopreventive agent as it reduces the cancer risk in ulcerative colitis patients. The current study analyses the effect of 5-ASA on Wnt/β-catenin signaling in vitro and in vivo in colon epithelial cells. The effect of 5-ASA was determined using a β-catenin/T-cell factor (TCF)-reporter assay and by western blotting in cultured colon cancer cells. Formalin fixed paraffin embedded material from 227 polyps removed from a subgroup of 56 patients, who participated in a randomized placebo-controlled 3-year prevention trial with 5-ASA was evaluated according to histomorphological characteristics and expression of β-catenin and target genes Cox2, cyclin D1 and E-cadherin as well as ornithine decarboxylase (ODC). Patients were grouped into a low-risk and a high-risk group according to the number of adenomas at initial colonoscopy. ß-catenin/TCF signaling activity was significantly reduced by 5-ASA treatment possibly through a reduction in ß-catenin levels. Moreover, 5-ASA significantly reduced ß-catenin levels and nuclear localization in patients' adenomas. In addition, 5-ASA also significantly changed expression of the downstream targets Cox2, cyclin D1 and E-cadherin, correlating with ß-catenin status. Moreover, 5-ASA significantly reduced levels of ODC in vivo. Expression of p53 was unaltered by the 5-ASA treatment. Our study shows a significant in vitro and long-term in vivo effect of 5-ASA on ß-catenin signaling as a key signaling pathway in the development of colorectal adenoma. Therefore, we suggest the use of 5-ASA as a promising drug for prevention of sporadic colorectal carcinoma.

Gastrointestinal bleeding from small-bowel varices is a rare and difficult to treat complication of portal hypertension. We describe the case of a 79-year-old female patient with recurrent severe hemorrhage from small-bowel varices 30 years after a complicated cholecystectomy. When double balloon enteroscopy was unsuccessful to reach the site of bleeding, a rendezvous approach was favored with intraoperative endoscopy. Active bleeding from varices within a biliodigestive anastomosis was found and controlled by endoscopic injection of cyanoacrylate. Intraoperative endoscopy should be considered in the case of life-threatening gastrointestinal hemorrhage that is not accessible by conventional endoscopy.

Hepatitis C ist eine durch das Hepatitis-C-Virus (HCV) verursachte Infektionskrankheit. Die Übertragung erfolgt über das Blut; Risikofaktoren für eine Infektion waren bis 1992 häufig Bluttransfusionen und Hämodialyse, heute in erster Linie ein Drogenabusus. Hepatitis C wird nur selten im akuten Stadium diagnostiziert, da die Infektion meist symptomlos oder nur mit milden, unspezifischen Symptomen wie Abgeschlagenheit und Müdigkeit verläuft. In 60-80% der Fälle nimmt die Erkrankung einen chronischen Verlauf. Die Diagnose der Hepatitis C erfolgt über den Nachweis von HCV-Antikörpern mittels Enzymimmunoassay (EIA) und HCV-RNA im Serum mittels Polymerase-Kettenreaktion (PCR). Eine Leberbiopsie ermöglicht eine Aussage über das Stadium der Erkrankung. Die Therapie der chronischen Hepatitis erfolgt derzeit mit einer Kombination aus einem pegylierten Interferon und dem Virostatikum Ribavirin. Die Therapieantwort ist abhängig vom Genotyp des Virus, der Viruslast und Viruskinetik unter der Therapie. In 15-20% der Fälle entwickelt sich mehr als 20 Jahre nach der Erstinfektion eine Leberzirrhose.

SummaryThe acute hepatic porphyrias can cause life‐threatening attacks of neurovisceral symptoms that mimic other acute medical conditions. Variegate porphyria caused by mutations in the protoporphyrinogen oxidase (PPOX) gene is a latent disorder characterized by exacerbations induced by fasting, alcohol consumption or certain drugs. We describe the case of a 46‐year‐old female patient presenting with a first episode of symptomatic porphyria after 10 d of sibutramine treatment for weight loss. Genetic analysis showed a heterozygous R168H hot spot mutation in the PPOX gene. A putative effect of sibutramine on the hepatic haem biosynthetic pathway and reduced food intake have likely caused this exacerbation of a porphyria attack. Although this may be the first case report of this kind, the risk of acute porphyria should be considered in patients using pharmacotherapy for obesity.

The existence of multiple HCV genotypes characterized by marked sequence differences is a challenge for immune control.The aim of this study is a comparison of the antiviral CD8 T cell response targeting HCV genotype 1 and genotype 3 antigens to determine the extent of cross-genotype reactivity of HCV-specific T cells.We analyze a cohort of patients with past or ongoing intravenous drug use hypothesizing that multiple exposures to different genotypes may occur.Methods: HCV-specific T cells are expanded from PBMC in the presence of peptide pools covering NS3 consensus sequences from genotype 1 or 3. Individual reactive peptides are determined by intracellular cytokine staining of IFNg.NS3 is amplified by PCR and sequenced from all viremic patients.Results: 53 subjects were analyzed; this includes 17 subjects infected with HCV genotype 1, 22 subjects infected with HCV genotype 3 and 14 anti-HCV-positive subjects with undetectable viremia.A total of 29 distinct epitopes (58 CD8 responses) was identified with significantly more and stronger CD8 responses in subjects with undetectable viremia.Of note, 14 epitopes (48.3%) were exclusively detected with genotype 1 peptides and not cross-reactive with the genotype 3 sequence.In turn, 7 (24.1%)epitopes were exclusively detected with genotype 3 peptides.Only, seven CD8 epitopes (24.1%) were cross-reactive in both genotypes including four epitopes where the targeted peptide sequence is identical in both genotypes and additional three epitopes with different consensus sequences both being fully cross-reactive.A novel HLA-B13-restricted epitope identified in three subjects was particularly interesting.Although T cells directed against the genotype 1 and the genotype 3 sequence were detected, two T cell populations each specific for one genotype only coexisted in all three subjects.Importantly, HCV-specific T cells reactive with both genotypes were predominantly identified in HCV-RNA negative subjects. Conclusion:The majority of HCV-specific CD8 epitopes identified in individuals with intravenous drug use have only limited cross-genotype reactivity.Importantly, CD8 T cells reactive against genotypes 1 and 3 were predominantly identified in subjects with undetectable HCV-RNA potentially characterizing a subgroup of patients being protected from chronic infection despite repetitive exposures to different HCV genotypes.

Background BILB 1941 is a potent and specific non-nucleoside inhibitor of the hepatitis C virus (HCV) RNA polymerase in vitro. Methods In a double-blind sequential group comparison, 96 male HCV genotype 1 patients with minimal to mild liver fibrosis (Ishak or Metavir score 0–2) were randomized (8 to active treatment and 2 to placebo per dose group) and treated with 10–450 mg BILB 1941 every 8 h over 5 days. Viral load (VL) was measured using Roche Cobas TaqMan® assays. Results VL decreased by ≥1 log10 IU/ml in 2/8, 2/8, 1/8, 2/7, 0/8, 2/8 and 4/5 patients on 60, 80, 100, 150, 200, 300 and 450 mg, respectively. No response was seen with placebo. HCV subtype 1b showed better response than 1a, the effect of other covariables including prior interferon treatment was not significant. NS5B population sequencing and phenotyping identified baseline samples with reduced BILB 1941 susceptibility, but did not detect an on-treatment emergence of resistant mutants. Plasma drug levels were linear until 300 mg. No serious adverse events (AEs) were reported. AEs were mainly gastrointestinal-related (most frequent diarrhoea) and frequency increased with dose. On 450 mg, all five active-treated patients discontinued (four for gastrointestinal intolerance and one for increased aspartate aminotransferase and alanine aminotransferase levels) and the trial was discontinued. Conclusions BILB 1941 monotherapy demonstrated antiviral activity against HCV genotype 1, but gastrointestinal intolerance precluded testing of higher doses.

Meyer HE1, Molleken2 C, Sitek B1, Henkel C1, Poschmann G1, Sipos B3, Wiese S1, Warscheid B1, Broelsch C4, Reiser M2, Friedman SL5, Tornoe I6, Schlosser A6, Kloppel G3, Schmiegel W2,7, Holmskov U6, und Stuhler K1 1Medizinisches Proteom-Center, Ruhr-Universitat Bochum, Germany; 2Department of Internal Medicine, Bergmannsheil, Ruhr-Universitat Bochum, Germany; 3Department of Pathology, Christian Albrechts University, Kiel, Germany, 4Department of General Surgery and Transplantation, University Hospital, Essen, Germany; 5Division of Liver Diseases, Mount Sinai School of Medicine, New York, USA; 6Department of Medical Biology, University of Southern Denmark, Odense, Denmark; 7Department of Internal Medicine, Knappschaftskrankenhaus, Ruhr-Universitat Bochum, Germany