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Introduction: In 15% of patients with iron deficiency anemia, large diaphragmatic hernias are found as the cause of chronic iron loss. Conversely, iron deficiency anemia is present in 10–40% of diaphragmatic hernia patients. However, it is unclear why some patients with large diaphragmatic hernias develop anemia and others do not. Methods: We retrospectively analyzed 116 patients with diaphragmatic hernias larger than 5 cm for the presence of anemia and the effect of surgery on this anemia, dividing these patients into 4 groups (group A: 21 patients with anemia/surgery, group B: 27 patients without anemia but with surgery, group C: 34 patients with anemia but without surgery, and group D: 34 patients without anemia/surgery). Results: Women significantly predominated in the patient population (76%). Patients with iron deficiency anemia tended to be significantly older than patients without iron deficiency anemia (74.7 ± 12.2 vs. 69.6 ± 14.8 years, p = 0.08). The proportion of patients taking ASA was significantly higher in the anemia collective (41.8% vs. 9.8%, p < 0.001). Regression analysis further confirmed that higher age and ASA intake correlated significantly with lower hemoglobin in anemic patients. Performing hernia repair significantly decreased anemia rates and PPI use in the anemia patients, while both remained almost the same in the non-operated anemia patients. Conclusion: ASA use and advanced age are risk factors for the presence of iron deficiency anemia in patients with large diaphragmatic hernias. Surgical hernia repair is suitable to reduce anemia.

Background Chronic pain represents a significant and costly healthcare problem especially in the older patient. Transdermal opioid therapy is easy to apply and ensures constant supply of active ingredients. However, skin irritation, poor adhesion and systemic side effects complicate transdermal pain therapy. Methods In the Relief study, comprising 54 centers, all in Germany, 252 patients were recruited and data about the general care situation as well as the characteristics, effects and side effects of the Aloe vera fentanyl patch were collected. 92 patients had a prior treatment with fentanyl patch without Aloe vera, allowing a comparative analysis. Results Compared to patches without Aloe vera, the new fentanyl patch showed better adhesion. Systemic and local tolerance and pain reduction were also significantly better. Patients also reported improvements in side effects and central parameters of quality of life. The data regarding the care situation in Germany showed remarkably low use of coanalgetics and laxatives in pain patients. Discussion Aloe vera in transdermal pain treatment improves adhesion and local tolerance of the patch. Pain control and quality of life were also improved. Regional care data concerning cotreatment in pain therapy from this study indicate a lack of penetration of existing guidelines in general practitioners’ pain therapy.

Percutaneous endoscopic gastrostomy is an established method to provide nutrition to patients with restricted oral uptake of fluids and calories. Here, we review the methods, indications and complications of this procedure. While gastrostomy can be safely and easily performed during gastroscopy, the right patients and timing for this intervention are not always chosen. Especially in patients with dementia, the indication for and timing of gastrostomies are often improper. In this patient group, clear data for enteral nutrition are lacking; however, some evidence suggests that patients with advanced dementia do not benefit, whereas patients with mild to moderate dementia might benefit from early enteral nutrition. Additionally, other patient groups with temporary or permanent restriction of oral uptake might be a useful target population for early enteral nutrition to maintain mobilization and muscle strength. We plead for a coordinated study program for these patient groups to identify suitable patients and the best timing for tube implantation.

Introduction: Since conservative antibiotic treatment in uncomplicated appendicitis might not solve the clinical problem definitively, it has to compete with the results of today’s laparoscopic appendectomy. Methods: In a county hospital, accommodating also a pediatric department, all cases of appendectomy for suspected appendicitis over 15 years were analyzed retrospectively for the following items: beginning of symptoms, time from admission to surgery, surgical technique as “open,” “laparoscopic” or “converted,” if perforated at operation and histological confirmation of acute inflammation. Surgical morbidity was detected in distinct categories. To evaluate changes over time, 3 time periods of 5 years each were defined. Results: Resulting in a total of 1,956 cases there were 731 in group I, 633 in group II and 592 in group III within the 3 time periods, respectively. The median age was 17 years. The percentage of perforations was 16.8%. Those patients had – with 47 compared to 27 h – a significantly prolonged time from the beginning of symptoms to admission (p = 0.0001). The proportion of laparoscopic surgery rose from 83.3 (group I) to 98.3% (group III; p = 0.0001). The median postoperative hospital stay diminished from 4 to 3 days in nonperforated (p = 0.0001) and from 8 to 7 days in perforated cases (p = 0.0009). Surgical morbidity was reduced from 4.1% in the first to 1.7% in the third observation period (p = 0.0144). There were no surgical site infections during the last 5 years. Conclusions: Timely laparoscopic appendectomy in case of suspected appendicitis can be offered with an extraordinary low morbidity. Taking into account the complete solution of the otherwise pending threat, compared to conservative antibiotic treatment, it is safe and definitive.

The incidence of non-alcoholic fatty liver disease (NAFLD) is rising, especially in Western countries. Drug treatment in patients with NAFLD is common since it is linked to other conditions like diabetes, obesity, and cardiovascular disease. Consequently, changes in drug metabolism may have serious clinical implications. Areas covered: A literature search for studies in animal models or patients with obesity, fatty liver, non-alcoholic steatohepatitis (NASH) or NASH cirrhosis published before November 2016 was performed. After discussing epidemiology and animal models for NAFLD, we summarized both basic as well as clinical studies investigating changes in drug transport and metabolism in NAFLD. Important drug groups were assessed separately with emphasis on clinical implications for drug treatment in patients with NAFLD. Expert opinion: Given the frequency of NAFLD even today, a high degree of drug treatment in NAFLD patients appears safe and well-tolerated despite considerable changes in hepatic uptake, distribution, metabolism and transport of drugs in these patients. NASH causes changes in biliary excretion, systemic concentrations, and renal handling of drugs leading to alterations in drug efficacy or toxicity under specific circumstances. Future clinical drug studies should focus on this special patient population in order to avoid serious adverse events in NAFLD patients.

Percutaneous endoscopic gastrostomy is an established method to provide nutrition to patients with restricted oral uptake of fluids and calories. Here, we review the methods, indications and complications of this procedure. While gastrostomy can be safely and easily performed during gastroscopy, the right patients and timing for this intervention are not always chosen. Especially in patients with dementia, the indication for and timing of gastrostomies are often improper. In this patient group, clear data for enteral nutrition are lacking; however, some evidence suggests that patients with advanced dementia do not benefit, whereas patients with mild to moderate dementia might benefit from early enteral nutrition. Additionally, other patient groups with temporary or permanent restriction of oral uptake might be a useful target population for early enteral nutrition to maintain mobilization and muscle strength. We plead for a coordinated study program for these patient groups to identify suitable patients and the best timing for tube implantation.

The influence of singing activities and breathing exercises on the presence of gastroesophageal reflux disease (GERD) symptoms is not clear. While an Austrian study found symptom reduction, an Italian study showed more symptoms in professional opera choristers. These contradictory results may be due to differential intensity of the singing exercises. We therefore developed a questionnaire to investigate the presence of GERD typical symptoms and defined GERD in nonprofessional choristers with moderate singing activity and breathing exercises and compared the results to those from related non-singing control persons. 434 actively engaged lay-choir persons and 310 non-singing friends or relatives answered questions in a questionnaire regarding basic data, singing habits, GERD symptoms, and past or present diagnostic events and medications. Non-singing control persons experienced more frequently heartburn (1.1 ± 4.1 vs. 0.5 ± 1.2 episodes/week, p = 0.001) and acid regurgitation (0.9 ± 4.1 vs. 0.5 ± 1.3 episodes/week, p 0.001) and had more often already received the diagnosis of GERD (16.8 % vs. 10.4 %, p = 0.011). From the persons without known GERD, members of the control cohort more often fulfilled the simplified diagnostic criteria of GERD (14.3 % vs. 5.1 %, p 0.001). A multivariate analysis identified non-singing, high body mass index, and smoking as significant risk factors for the presence of GERD symptoms. The frequency of reflux symptoms and GERD is probably still increasing. Moderate singing activities and breathing exercises seem to be helpful in avoiding reflux symptoms such as heartburn and acid regurgitation. Singaktivitäten und Atemübungen können über eine Kräftigung der Zwerchfellschenkel den unteren Ösophagussphinkter stärken und, wie in einer kleinen Grazer Studie gezeigt, auch Refluxsymptome lindern. Andererseits berichten zahlreiche Fallstudien und eine Kohortenstudie über vermehrten Reflux insbesondere bei professionellen Opernsängern, z. T. in Abhängigkeit von der Intensität und zeitlichen Ausdehnung der Singaktivitäten. In einer Kohortenstudie befragten wir 434 im Laien-Chor mit Sing- und Atemübungen aktive Personen (Alter 55,1 ± 15 Jahre, 46,7 % männlich, BMI 25 ± 3,8) zu Refluxsymptomen, bekannter Refluxkrankheit (GERD) und Diagnostik und Therapie in diesem Zusammenhang. Eine Kontrollkohorte wurde aus 310 nicht-singenden Freunden und Familienangehörigen dieser Sänger gebildet (Alter 48,2 ± 17,7 Jahre, 47,9 % männlich, BMI 25,5 ± 6,3). Nicht-singende Kontrollpersonen hatten signifikant häufiger Sodbrennen (1,1 ± 4,1 vs. 0,5 ± 1,2 Ereignisse pro Woche) und saures Aufstoßen (0,9 ± 4,1 vs. 0,5 ± 1,3 Ereignisse pro Woche) und hatten häufiger bereits die Diagnose einer Refluxkrankheit erhalten (16,8 vs. 10,4 %) als singende Personen. Auch Personen ohne bekannte GERD erfüllten signifikant häufiger die rein klinisch-epidemiologische Definition der Refluxkrankheit in der Kontrollgruppe (14,3 vs. 5,1 %). Fast ein Drittel der Personen beider Kohorten wurde schon mindestens einmal gastroskopiert, zahlreiche Personen in beiden Gruppen hatten aus verschiedenen Gründen schon phasenweise Säureblocker eingenommen (20,3 % in der Chorgruppe, 29 % bei den Nicht-Sängern). In der multivariaten Analyse wurden ein Nikotinabusus, ein BMI 25 und das Nicht-Singen als unabhängige Determinanten für das Vorliegen von Sodbrennen identifiziert. Regelmäßiges, nur moderates Chorsingen mit Atemübungen scheint vor Sodbrennen und saurem Aufstoßen und damit vor GERD zu schützen.

The liver is the central place for the metabolism of drugs and other xenobiotics. In the liver cell, oxidation and conjugation of compounds take place, and at the same time, bile formation helps in extrusion of these compounds via the biliary route. A large number of transporters are responsible for drug uptake into the liver cell and excretion into bile or efflux to the sinusoidal blood.Genetic variants of these transporters and their transactivators contribute to changes in drug handling and are also responsible for cholestatic syndromes of different severity. This review summarizes the current knowledge regarding the influence of these genetic changes. The review covers progressive hereditary cholestatic syndromes as well as recurrent or transient cholestatic syndromes such as drug-induced liver injury, intrahepatic cholestasis of pregnancy, and benign recurrent intrahepatic cholestasis.Polymorphisms in transporter genes are frequent. For clinically relevant cholestatic syndromes, it often requires a combination of genetic variants or acquired triggers such as pregnancy or drug treatment. In combination with other pathogenetic aspects, genetic variants in drug transporters may contribute to our understanding of not only cholestatic diseases such as primary sclerosing cholangitis or primary biliary cirrhosis, but also the natural course of chronic liver disease in general.

In this edition of VISZERALMEDIZIN, we address an important medical subject in the best tradition of interdisciplinary expertise in gastrointestinal medicine and surgery, i.e. digestive insufficiency, maldigestion and malabsorption, as well as their causes, pathophysiology, and therapeutic approaches.

Introduction: In earlier studies, involvement of the small intestine was reported in patients with gastrointestinal lymphoma. Prospective data on the involvement of the small intestine in patients suffering from gastric extranodal MZBCL of MALT do not exist so far. In this study, we investigated the frequency of the involvement of the small intestine and the role of capsule endoscopy in patients with gastrointestinal extranodal MZBCL of MALT and of follicular lymphoma. Patients and Methods: 40 consecutive patients with gastrointestinal extranodal MZBCL of MALT (26 men, 14 women, aged 27 − 80 years), and 7 patients with known follicular lymphoma of the small intestine (5 men, 2 women, aged 34 − 63 years) underwent capsule endoscopy. Results: Involvement of the small intestine was identified by capsule endoscopy in all 7 patients with known follicular lymphoma of the small intestine. In 6 of 40 patients with gastric extranodal MZBCL of MALT abnormal findings could be observed, three of these findings indicative for lymphoma involvement of the small intestine. However, in each of these 3 cases, intestinal involvement had been already diagnosed by conventional GI endoscopy before capsule endoscopy. Conclusions: Capsule endoscopy is able to detect involvement of the small intestine in patients with gastrointestinal lymphoma. However, involvement of the small intestine seems to be rare in patients with gastric extranodal MZBCL of MALT. In summary, routine diagnostic work-up of the small intestine, e. g. by capsule endoscopy seems unnecessary because of the rare involvement of the small intestine and an excellent long-term outcome irrespective of a possible intestinal manifestation.

The German guideline for sedation in gastrointestinal endoscopy was published in 2008. Several recommendations in this guideline, especially concerning staffing and structural requirements for sedation, have low evidence and therefore are subject to discussion in the field.Comparison of endoscopic complications in a department specialized for gastrointestinal and pulmological diseases before and after implementation of the German guideline grouped in sedation-associated and non-sedation-associated complications.Prospective documentation of complications with retrospective analysis of two patient groups (before guideline: 1.5.2008-30.4.2010; after guideline: 1.5.2010-30.4.2012) at which the sedation technique remained the same (balanced propofol sedation, BPS).Both investigation periods covered almost 7000 procedures. Interventional and general complications were nonsignificantly elevated in the latter group (1.27% before vs. 1.55% after guideline, p = 0.08). Saturation decline (in both groups 0.26%) was unchanged, and circulation-associated complications (0.27% vs. 0.13%, p = 0.07) were reduced nonsignificantly. Necessity for the administration of flumazenil and for intensive care monitoring was reduced in a nonsignificant manner after the implementation of the guideline. Severe complications (reanimation, apnea, and death) were unchanged, and no patient with ASA I-II suffered from a severe complication. Propofol consumption was higher after guideline implementation.The recommendations of the new German sedation guideline do not significantly reduce complications in endoscopic procedures. Especially, procedures involving patients with ASA classes I and II do not require an additional staff member solely for sedation. Prospective randomized studies might be necessary to optimize the utilization of resources.

The majority of gastrointestinal lymphomas belongs to the group of the MALT (mucosa-associated lymphoid type) lymphomas arising in the stomach, therefore rendering them accessible to endoscopy. Staging currently follows the modified Ann Arbor classification but most likely in the future, the TNM-based Paris staging system will be applied due to its detailed description of the local spread as well as the extraintestinal dissemination. For assessment of gut wall infiltration and local lymphonodular involvement, endoscopic ultrasound currently represents the standard procedure and is an essential diagnostic tool regarding locoregional staging. Additionally, the method confers a high prognostic value regarding treatment response in MALT lymphoma. In endoscopic ultrasound stage EI 1, Helicobacter pylori eradication leads in 70 - 100 % to a complete response. However, the value of endoscopic ultrasound in the follow-up of lymphomas after chemotherapy remains elusive and controversial. There is no clear correlation between histologically proven residual disease and endosonographic results. Thus, so far, endoscopic ultrasound will not replace bioptic surveillance after MALT lymphoma treatment.

Hepatic uptake and biliary excretion of organic anions (e.g., bile acids and bilirubin) is mediated by hepatobiliary transport systems. Defects in transporter expression and function can cause or maintain cholestasis and jaundice. Recruitment of alternative export transporters in coordination with phase I and II detoxifying pathways provides alternative pathways to counteract accumulation of potentially toxic biliary constituents in cholestasis. The genes encoding for organic anion uptake (NTCP, OATPs), canalicular export (BSEP, MRP2) and alternative basolateral export (MRP3, MRP4) in liver are regulated by a complex interacting network of hepatocyte nuclear factors (HNF1, 3, 4) and nuclear (orphan) receptors (e.g., FXR, PXR, CAR, RAR, LRH-1, SHP, GR). Bile acids, proinflammatory cytokines, hormones and drugs mediate causative and adaptive transporter changes at a transcriptional level by interacting with these nuclear factors and receptors. Unraveling the underlying regulatory mechanisms may therefore not only allow a better understanding of the molecular pathophysiology of cholestatic liver diseases but should also identify potential pharmacological strategies targeting these regulatory networks. This review is focused on general principles of transcriptional basolateral and canalicular transporter regulation in inflammation-induced cholestasis, ethinylestradiol- and pregnancy-associated cholestasis, obstructive cholestasis and liver regeneration. Moreover, the potential therapeutic role of nuclear receptor agonists for the management of liver diseases is highlighted.

Matrix metalloproteinases (MMPs) are responsible for the turnover and degradation of extracellular matrix. They play a crucial role in the growth and migration of colorectal carcinoma cells. Colorectal carcinomas are characterized by enhanced expression of MMP-2, MMP-9, MMP-7, and MMP-13. The aim of this study was to determine the expression levels of MMP-2, MMP-9, MMP-7, MMP-13, and MMP-14 and their specific inhibitor TIMP-1 in inflammatory bowel diseases and precancerous lesions of the colon, i.e., Crohn's disease and ulcerative colitis, and in adenomatous polyps (APs) for comparison. Biopsy samples of pathological and healthy tissue were obtained from 40 patients with inflammatory bowel disease (ulcerative colitis, n = 17; Crohn's disease, n = 23) and from 19 patients with APs. mRNA was measured by quantitative real-time polymerase chain reaction to study MMP and TIMP-1 gene expression in both pathological and normal mucosal specimens. For MMP-2, MMP-9, and TIMP-1, protein expression also was quantified with sandwich enzyme-linked immunosorbent assay. In biopsy specimens of Crohn's disease and ulcerative colitis, significantly increased levels of MMP-2, MMP-7, and MMP-13 mRNA were found. MMP-2 and MMP-9 showed enhanced secretion on the protein level. AP revealed an increased transcription of MMP-7 and MMP-13 genes. MMP-14 mRNA was decreased in APs. MMPs, especially MMP-7 and MMP-13, which are expressed primarily on the tumor cell surface, are elevated in inflammatory bowel disease, which may have more chance to evolve into malignancy than normal tissue. In APs, increased expression of MMP-7 and MMP-13 may serve as an early indicator for colorectal carcinogenesis.

BACKGROUND: We report the case of a 43-year-old male with liver cirrhosis based on a chronically active hepatitis C. CASE REPORT: Before liver transplantation right-ventricular pressure values of 36 mmHg (+ central venous pressure) were measured whereas, after transplantation, he developed severe pulmonary hypertension with pressure values up to 90 mmHg. These elevated pressure values correlated inversely with graft function. Given the diagnosis of portopulmonary hypertension, we initiated treatment with intravenous epoprostenol and inhalative iloprost but both treatments were not tolerated because of systemic side effects. A combined heart-lung transplantation was considered but the patient died from insufficient cardiac function. CONCLUSIONS: The case report discusses the present diagnostic and therapeutic state of the art in portopulmonary hypertension and reveals basic problems of the present screening strategy.

Proinflammatory cytokines such as TNF-alpha and IL-1beta lead to downregulation of hepatic organic anion transporters in cholestasis. This adapted response is transcriptionally mediated by nuclear hormone receptors and liver-specific transcription factors. Because little is known in vivo about cytokine-dependent regulatory events, mice were treated with either TNF-alpha or IL-1beta for up to 16 h. Transporter mRNA expression was determined by Northern blot analysis, nuclear activity, and protein-expression of transactivators by EMSA and Western blotting. TNF-alpha induces a sustained decrease in Ntcp, Oatp1/Oatp1a1, and Bsep mRNA expression but exerts only transient [multidrug resistance-associated protein 2 (Mrp2)] or no effects (Mrp3) on Mrps. In addition to Ntcp and Oatp1/Oatp1a1, IL-1beta also downregulates Bsep, Mrp2, and Mrp3 mRNAs to some extent. To study transcriptional regulation, Ntcp and Bsep promoters were first cloned from mice revealing a new distal Ntcp hepatocyte nuclear factor 1 (HNF-1) element but otherwise show a conserved localization to known rat regulatory elements. Changes in transporter-expression are preceeded by a reduction in binding activities at IR-1, ER-8, DR-5, and HNF-1alpha sites after 4 h by either cytokine, which remained more sustained by TNF-alpha in the case of nuclear receptors. Nuclear protein levels of retinoid X receptor (RXR)-alpha are significantly decreased by TNF-alpha but only transiently affected by IL-1beta. Minor reductions of retinoic acid receptor, farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor nuclear proteins are restricted to 4 h after cytokine application and paralleled by a decrease in mRNA levels. Basolateral and canalicular transporter systems are downregulated by both cytokines, TNF-alpha and IL-1beta. Activity of HNF-1alpha as regulator of mNtcp is suppressed by both cytokines. Decreased binding activities of nuclear receptor heterodimers may be explained by a reduction of the ubiquitous heterodimerization partner RXR-alpha.

Cholestatic liver injury is associated not only with accumulation of bile acids but also with activation of proinflammatory cytokines. Common bile duct ligation (CBDL) induces sustained downregulation of the Na(+)/taurocholate cotransporter (Ntcp) in rodent liver. Although repression of Ntcp during endotoxemia is cytokine mediated, it is unclear whether inflammatory cytokines contribute to this downregulation in obstructive cholestasis. Cytokine inactivation in CBDL rats and mice was either performed directly with tumor necrosis factor alpha (etanercept) or interleukin 1 beta inactivation (anakinra/AMG 719) or indirectly Kupffer cell depletion via intraperitoneal administration of liposome-encapsulated dichloromethylene bisphosphonate. Protein and messenger RNA (mRNA) expression of Ntcp and short heterodimer partner (SHP) were analyzed via Western and Northern blotting. Key regulators of Ntcp (hepatocyte nuclear factor 1 alpha [HNF-1alpha], HNF-4alpha, retinoid X receptor alpha [RXRalpha]:retinoic acid receptor alpha [RARalpha]) were studied via electrophoretic mobility shift analysis and nuclear Western blot analysis. Both methods of cytokine inactivation failed to maintain Ntcp protein or mRNA expression within 3 days after CBDL in either rats or mice (20%-40% of sham controls), while SHP mRNA expression increased three- to five-fold. Decreased nuclear HNF-1alpha and HNF-4alpha protein levels (45% and 60% of sham controls, respectively) and HNF-1alpha binding activity (32% of sham controls) were not restored during cytokine inactivation after CBDL, indicating cytokine-independent mechanisms of Ntcp regulation. RXRalpha:RARalpha binding remained unchanged in all experimental conditions. In conclusion, during obstructive cholestasis accumulating bile acids per se, without major contribution of cytokines, leads to downregulation of Ntcp via repression of HNF-1alpha and HNF-4alpha.

Background & Aims: Multidrug resistance-associated protein 2 (MRP2), a transporter of organic anions in hepatocytes, renal epithelial cells, and enterocytes, is differentially regulated in liver and kidney during cholestasis, but little is known about its regulation in the intestine. Methods: We investigated duodenal protein expression of MRP2 in male Sprague-Dawley rats with bile duct ligation (BDL) or biliary diversion as well as in 20 cholestatic patients with biliary obstruction. Results: In biliary obstruction, but not biliary depletion, intestinal Mrp2 protein mass was reduced to 9.3% +/- 5.5% of controls and mRNA to 40.5% +/- 20.8% of controls after 7 days. Binding of RXRalpha:RARalpha heterodimers to the Mrp2 promoter element was significantly reduced in BDL rats. Cytokine blockade identified IL-1beta as the responsible inducer of Mrp2 down-regulation. In humans with obstructive cholestasis, intestinal MRP2 protein expression was reduced to 27.3% +/- 20.3% of control patients; this reduction correlated with the duration of cholestasis and was reversible after reconstitution of bile flow by stenting of the common bile duct. However, no significant differences in MRP2 mRNA levels were detected by RT-PCR in humans. Intestinal protein expression of P-glycoprotein, breast cancer resistance protein (BCRP), and MRP3 was unchanged. In BDL rats, oral bioavailability of the Mrp2 substrate and food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was elevated 2.5 times compared with sham-operated rats. Conclusions: Cholestasis promotes down-regulation of MRP2 expression in the duodenum of rats and humans. Selective down-regulation during cholestasis might be the consequence of species-specific transcriptional and posttranscriptional mechanisms and contributes to higher bioavailability of a food-derived carcinogen

Three cases of gastrointestinal stromal tumors (GIST) are reported as typical examples of the broad clinical spectrum in which these rare tumors can be detected. The first case describes an 82-year-old patient with a hemorrhagic shock due to upper gastrointestinal bleeding from a GIST of the stomach. GIST most frequently present with either gastrointestinal bleeding, abdominal pain or a detectable mass on physical examination or by ultrasound imaging. Clinically asymptomatic tumor growth also occurs as demonstrated by the second case of a 44-year-old -woman with an incidental finding of GIST during surgery of the esophagus. The cases are used to discuss the consequences for therapy and prognosis resulting from the heterogeneity of this tumor entity; the relevant immunohistochemical markers used to distinguish between various tumor subtypes of gastrointestinal mesenchymal tumors (GIMT) are listed. Since gastrointestinal stromal tumors (GIST) represent the most common subgroup of GIMT, we focus on the clinicopathological prognostic factors of GIST. The third case of a 40-year-old patient with a malignant GIST recurrence after surgery and exhibiting secondary resistance after one year of successful therapy with the receptor tyrosine kinase inhibitor imatinib (Gleevec), antagonizing pathogenetically relevant constitutive c-KIT activation, illustrates the potential and limitations of the only effective drug treatment for advanced GIST.

Das Zytomegalievirus (CMV) verursacht bei immunsupprimierten Patienten erhebliche Morbiditat und Mortalitat, wahrend es bei Immunkompetenten in der Regel zu oligo- oder asymptomatischen klinischen Verlaufen kommt. Berichtet wird uber einen 54-jahrigen immunkompetenten Patienten mit dem klinischen Vollbild der CMV-Mononukleose und Begleithepatitis, wobei die Symptomatik mit erheblicher Reduktion des Allgemeinzustandes und hochfebrilen Temperaturen ungewohnlich lange anhielt und erst die intravenose Therapie mit Ganciclovir zu rascher Beschwerdefreiheit fuhrte. Diesem Fall wird eine 31-jahrige Frau gegenubergestellt, bei der ein mittelgradig ausgepragtes mononukleoseahnliches akutes Krankheitsbild in der Schwangerschaft nach Kontakt mit einem CMV-erkrankten Saugling auftrat. Bei Schwangeren ist die korrekte Diagnosestellung einer Primar- oder Sekundarinfektion mit CMV bzw. deren Ausschluss wegen des Risikos einer konnatalen CMV-Infektion besonders wichtig, und die zweite Kasuistik zeigt die dabei auftretenden diagnostischen Schwierigkeiten und Fallstricke auf. Die Fallbeispiele verdeutlichen, dass auch bei immunkompetenten Patienten und Schwangeren mit den Symptomen eines viralen Infekts eine CMV-Infektion in der Differentialdiagnose berucksichtigt werden sollte. Vor allem fur Schwangere und Organtransplantierte sind wegen moglicher Folgekomplikationen (konnatale CMV-Infektion, Transplantatversagen) eine fruhzeitige Diagnose und die Verfugbarkeit prognostischer Marker fur den zu erwartenden klinischen Verlauf wunschenswert.

Background and aims: The liver is the central organ for the detoxification of numerous xenobiotics, including carcinogens. We studied the influence of cholestasis and biliary cirrhosis on the detoxification, elimination, and tissue distribution of a model compound and food derived carcinogen, 2-amino-1-methyl- 6-phenylimidazo[4,5-b] pyridine (PhIP). Methods: Wistar rats were injected with C-14-PhIP into the portal vein one or six weeks after common bile duct ligation (CBDL). Bile flow was reconstituted, bile and urine were collected over 120 minutes, and metabolites were analysed using high performance liquid chromatograpy. Total tissue radioactivity levels in several organs as well as tissue bound ( ethanol insoluble tissue fraction) radioactivity levels were determined. Results: Significant downregulation of the transport proteins multidrug resistance associated protein 2 and breast cancer resistance protein was observed in biliary cirrhosis. Biliary excretion of radioactivity was significantly reduced in cholestasis and biliary cirrhosis compared with controls ( 15 (2.9)% and 3.2 ( 1)% of the dose v 36.5 ( 2)%, respectively). Phase II metabolism was severely reduced in cirrhotic rats, resulting in a twofold increase in tissue radioactivity levels in the liver, kidney, and colon. Biliary cirrhosis increased tissue binding of reactive metabolites, as expressed in cpm/100 mg tissue in the liver and the colon ( 3267 ( 1218) v 1191 ( 429) in the liver, 3044 ( 1913) v 453 ( 253) in the colon). Conclusions: Biliary cirrhosis induced by CBDL causes impaired metabolism and elimination of PhIP, and leads to higher tissue levels of potentially genotoxic metabolites in the liver and colon of rats. These data may explain the increased incidence of hepatic and extrahepatic cancers in cholestasis and liver cirrhosis

Recently CC chemokine receptor 5 (CCR5) related immune mechanisms and a functional mutation of the CCR5 gene have been implicated in hepatitis C virus (HCV) infection in a cohort of predominantly hemophiliac patients. The present study investigated the frequency and clinical consequences of the CCR5 Delta32 mutation in two genetically homogeneous populations of HCV infected patients with a different risk profile for infection. Genomic DNA samples from 333 German patients with chronic HCV infection were screened by PCR for the presence of the CCR5 Delta32 polymorphism. In-hospital patients admitted for other diseases than viral hepatitis but with a comparable risk for HCV exposure were used as control population ( n=125). Allele frequencies of CCR5 Delta32 polymorphism did not differ significantly between the two groups (7.6% and 9.5%, respectively) and control subjects (10.4%), and did not deviate from Hardy-Weinberg equilibrium in any group. Furthermore, there were no major differences between patients with respect to HCV genotypes, viral loads, liver enzymes, or fibrosis scores in relation to the presence or absence of the heterozygous CCR5 Delta32 mutation. Differences in inflammatory scores in liver biopsy samples and response to antiviral therapy in CCR5 Delta32 heterozygotes in one cohort could neither be reproduced in the other group of patients nor when both cohorts were pooled. These results argue against a strong effect of the CCR5 Delta32 deletion regarding these phenotypes. In conclusion, we found no increased frequency of the CCR5 Delta32 polymorphism in two independent cohorts of patients with HCV infection but without hemophilia as the main risk factor for infection. As the major difference to investigations demonstrating an association between CCR5 Delta32 and HCV infection is the selection of cases and controls, our study emphasizes the importance of epidemiological criteria for association studies of HCV infection.

Hintergrund: Die Cholestase ist ein atiologisch vieldeutiges Syndrom, das eine breite Differentialdiagnostik erfordert. Anhand von Anamnese, korperlicher Untersuchung, klinisch-chemischer Diagnostik und Sonographie ist eine Unterscheidung zwischen extrahepatischer und intrahepatischer Cholestase bei der Mehrzahl der Patienten moglich. Die vorliegende Ubersicht fasst den aktuellen Stand der Diagnostik cholestatischer Erkrankungen zusammen.

Multidrug resistance-associated protein 2 (MRP2, gene nomenclature ABCC2), a member of the family of ATP-binding cassette (ABC-) transporters, is present in the canalicular membrane of hepatocytes and in the apical membrane of enterocytes and renal tubule epithelial cells. At all of these barriers, MRP2 contributes to reduction of the body load of potentially toxic xenobiotics and endogenous waste products. This important “gatekeeper” function of MRP2 has been recognized recently, and data regarding this function are reviewed here. In its function at these barriers, MRP2 is part of a complex detoxification pathway that is regulated by nuclear receptors as common activators. However, MRP2 also can mediate toxicity by concentrating toxicants in the biliary duct and reducing the bioavailability of protective compounds.

Primary sclerosing cholangitis (PSC) is a cholestatic liver disease of unknown etiology. Although the primary defect affects cholangiocytes, cholestatic injury of hepatocytes may promote further liver damage. Since down-regulation of hepatocellular organic anion transporters is implicated in the molecular pathogenesis of cholestasis, expression of these transporters was determined in a novel rat model, which closely resembles human PSC.Hepatic protein and mRNA expression of basolateral (Ntcp, Oatp1, 2 and 4) and canalicular (Mrp2, Bsep) organic anion transporters were analyzed 1, 4 and 12 weeks after induction of experimental PSC by 2,4,6-trinitrobenzenesulfonic acid (TNBS).Specific down-regulation of basolateral and canalicular transport systems except Oatp4 and Bsep proteins occurred during the acute phase of inflammation. In chronic cholangitis 12 weeks after TNBS Mrp2 protein and mRNA remained down-regulated by 40-50% of controls (P0.05). In addition Oatp1 protein was also reduced by 40+/-13% (P0.05), whereas all other transporters returned to control values.In chronic cholangitis only canalicular Mrp2 expression remained down-regulated. This might represent the first injury to hepatocytes in chronic cholangitis as an extension of liver injury from the level of cholangiocytes to hepatocytes in PSC.

Hintergrund: Heterophile Antikorper konnen aufgrund immunologischer Interferenzen reproduzierbar falsch positive Laborwerte verursachen, die eine besondere Gefahr fur Diagnostik und Therapie darstellen. Dabei ist das Vertrauen des Klinikers in die Spezifitat des jeweiligen Laborwertes, gepaart mit fehlender Kommunikation mit Laborarzten, eine der haufigsten Ursachen fur unnotige diagnostische und therapeutische Masnahmen aufgrund dieses Phanomens. Die Pravalenz heterophiler Antikorper ist wahrscheinlich erheblich hoher als gemeinhin angenommen wird. Aufgrund des Entstehungsmechanismus der Interferenz konnen theoretisch, zusatzlich zu den in der Literatur berichteten Fallen, zahlreiche Laborparameter betroffen sein. Ziel: Die vorliegende Ubersicht fasst in der Literatur geschilderte Falle zusammen, erlautert die mogliche Entstehung der Antikorper und erklart den Mechanismus, der zur Interferenz im Immunoassay fuhrt. Daruber hinaus sollen jedoch fur den Kliniker relevante Aspekte wie Verbreitung und klinische Gegenmasnahmen angesprochen werden. Wichtigste Masnahme zur Verhinderung weiterer Patientenschaden durch heterophile Antikorper ist die Verbreitung des Wissens um diesen moglichen Storfaktor in immunologischen Assays.

While metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant food-derived heterocyclic amine and carcinogen, has been studied extensively in several species, transport of this compound and its metabolites has not been defined yet. Therefore we studied metabolism and disposition of PhIP in Wistar and Mrp2-deficient TR(-) rats to determine the role of Mrp2 in the defence against this compound. In the first 2 h after intravenous dosing, total excretion of PhIP and its metabolites in bile was > 4-fold reduced in TR(-) rats compared with Wistar rats, while excretion in the urine of the TR(-) rat was 1.8-fold higher. This difference was the result of an almost complete absence of secretion of glucuronidated metabolites but also a reduced level of secretion of unchanged PhIP into bile of the TR(-) rat. Direct intestinal excretion of unmetabolized PhIP was 3-fold higher in Wistar versus TR(-) rats. As a consequence, PhIP tissue levels in the liver were 1.7-fold higher in TR(-) rats, and tissue binding of PhIP, determined after ethanol extraction, was elevated by a similar magnitude. Mrp2-mediated transport of the parent compound PhIP is glutathione (GSH)-dependent, because GSH depletion by L-buthionine-[S,R]-sulfoximine (BSO) treatment in Wistar rats reduced intestinal secretion to the same level as that in TR(-) rats. TR(-) rats produced less glucuronides and 4'-OH-PhIP in the 2 h following PhIP administration. We conclude that Mrp2 protects against the carcinogen PhIP by biliary excretion of the parent compound and all major phase-II metabolites, but, more importantly, also by direct extrusion of the parent compound from the gut mucosa.

UDP-glucuronosyltransferases (UGTs) play an important role in detoxification of endo- and xenobiotics. Deficiencies of these enzymes can have serious consequences, for example, in Crigler–Najjar disease Type I. Recently it was shown that the activated form of the abundant food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is glucuronidated mainly by UGT1 isoforms. Therefore UGT1 deficiency may have an important impact on metabolism and excretion of PhIP in the body and consequently for the susceptibility toward carcinogenic effects through PhIP. To test this hypothesis we investigated fate and distribution of PhIP in the UGT1-deficient Gunn rat. In 2 h after intravenous injection of PhIP, Gunn rats excreted significantly more PhIP and metabolites than control animals, which were age- and weight-matched Wistar rats. In bile, both glucuronides of N-OH-PhIP were reduced but, in urine, only the N3-glucuronide was reduced while the N2-glucuronide was elevated. The metabolic pathway ratio between 4′-hydroxylation and N-hydroxylation was dramatically changed in the Gunn rat (five times higher in bile and doubled in urine, resulting in a four times higher ratio in total), mostly because of the doubled amount of 4′-PhIP-sulfate in Gunn rats compared to Wistar rats. Tissue levels of PhIP and metabolites were significantly lower in liver and colon of the Gunn rats. We conclude that, in Gunn rats, PhIP is alternatively metabolized through UGT2B enzymes and sulfotransferases, which adds another clue to the potential importance of sulfotransferases in detoxification of PhIP.

HISTORY AND CLINICAL FINDINGS A 81-year-old patient free of pain was referred to the university hospital for further evaluation and therapy of tumour masses in the right thorax. Clinical examination revealed dullness to percussion and reduced breathing in the right lower lung. INVESTIGATIONS Computed tomography showed an enlarged solid tumour mass attached to the thoracic cavity and pleural effusion on the right side. Quantification of pulmonary perfusion presented significant defects in the right upper and middle lobe. DIAGNOSIS, TREATMENT AND COURSE The pulmonary masses were biopsied under CT-guidance. Biopsy and immunohistochemical findings proved a malignant solitary fibrous tumour of the chest wall, a mesenchymal tumour of its own entity. Because of pain in the right arm and because of missing other reliable therapeutic options a palliative irradiation was performed. The tumour did increase in size due to radiotherapy and a severe right ventricular heart failure occurred. The patient died 5 months after diagnosis has been made. Autopsy revealed a transition of tumour cells to sarcomatic growth. CONCLUSION In our case we conclude an accelerated progression of the solitary fibrous chest wall tumour in the course of irradiation. Whether the development of sarcomatic growth occurred as a result of radiotherapy remains speculative.

We report the case of a 74-year-old lady who presented at our clinic with icterus and cholestatic hepatitis. For atrial fibrillation she had been prescribed a medication with phenprocoumone. After ruling out viral, autoimmune, and metabolic causes of hepatitis, we performed a liver biopsy which led to the diagnosis of phenprocoumone-related liver damage. The patient was discharged without phenprocoumone and completely compensated liver function. Five weeks later she returned to the hospital with encephalopathy, ascites, coagulopathy, varices, and signs of cirrhosis in abdominal ultrasound. In spite of treatment with steroids, the patient died of subacute liver failure several weeks later. This case illustrates the occasionally poor course of toxic hepatitis even after discontinuation of the responsible medication, potential treatment options are discussed.

To investigate the effect of Lactobacillus-containing commercially available probiotic formulations in Germany during antibiotic treatment with an analysis of cost-efficiency.In an observational study, we analyzed the frequency of bowel movements from 258 patients with infections in a primary care hospital in western Germany; 107 of the patients were offered a probiotic drink containing at least 10 billion cultures of Lactobacillus casei DN 114001 b.i.d. The economic analysis was based on the costs of patient isolation vs preventive intake of probiotics. In a second pilot study, two commercially available probiotic drinks with different Lactobacillus casei strains were directly compared in 60 patients in a randomized controlled fashion.In the first study, the incidence of antibiotic-associated diarrhea (AAD) was significantly reduced in the intervention group (6.5% vs 28.4%), and the duration of AAD in days was significantly shorter (1.7 ± 1.1 vs 3.1 ± 2.1). Higher age and creatinine and lower albumin were identified as risk factors for AAD. Ampicillin was the antibiotic with the highest rate of AAD (50%) and with the greatest AAD reduction in the probiotic group (4.2%, relative risk reduction 92%). The economic analysis showed a cost advantage of nearly 60000 €/year in a department of this size. The second study confirmed the preventive effect of the drink with Lactobacillus casei DN114001; however, there were no advantages found for the other tested probiotic drink containing Lactobacillus casei Shirota.In contrast to a drink containing Lactobacillus casei Shirota, a commercially available probiotic drink containing Lactobacillus casei DN 114001 cost-efficiently reduces the prevalence of AAD during antibiotic treatment.

We describe the case of a 36-years-old male patient, originating from India, who presented with enlarged cervical lymph nodes and elevated liver chemistry tests. Histologically necrosing granulomas were observed in the lymph nodes, and PCR revealed DNA from mycobacterium tuberculosis. However, in the liver biopsy granulomatous hepatitis without central necrosis was seen. With a positive PCR for mycobacteria from liver tissue and no evidence for other hepatic diseases we started drug treatment with standard quadruple regimen consisting of isoniazid, rifampicin, ethambutol, and pyrazinamide. Five days after onset of therapy, liver chemistry tests rose 10-fold, forcing us to interrupt treatment. Gradual step-wise re-exposition with the same medication after return of liver chemistry tests to baseline was well tolerated without any further side effects. Liver involvement of tuberculosis can have many facets and may be treated by gradual dosing of standard drugs.

Several molecular changes in colorectal adenomas provide the basis of the adenoma-carcinoma sequence. We investigated the expression of xenobiotic ATP-binding cassette (ABC) transporters in humans and in ApcMin mice and conducted functional studies estimating the importance of the expression changes. Twenty-nine adenomas from 21 patients and eight adenomas from four ApcMin mice were analyzed using Western blotting and quantitative Real-time polymerase chain reaction (RT-PCR). Adjacent healthy tissue served as control for each polyp. Breast cancer resistance protein (BCRP) was significantly downregulated in human colorectal adenomas (to 28 ± 35% of adjacent healthy tissue). This was in line with data from ApcMin mice adenomas, where downregulation was significant as well (to 58 ± 34%). In parallel, quantitative RT-PCR showed BCRP mRNA downregulation in human adenomas (to 17 ± 31%). Basal multidrug resistance-associated protein 2 expression was low and did not change in adenomas; multidrug resistance transporter 1 expression also did not differ between adenomas and healthy tissue. In a functional study, ApcMin mice received radioactively labelled 2-amino-1-methyl-6-phenylimidazo[4,5-β] pyridine (PhIP), a food colon carcinogen and substrate of BCRP, by oral gavage with analysis of PhIP accumulation and DNA adduct formation 48 hr later. In this setting, we could demonstrate a higher carcinogen concentration in adenomas of ApcMin mice (181 ± 113% of normal tissue) including immunohistochemical detection of PhIP-DNA adducts. We conclude that significant transcriptional downregulation of BCRP/Bcrp leads to higher carcinogen concentrations in colorectal adenomas of mice and men. This might promote the adenoma-carcinoma sequence by higher genotoxic effects. The results indicate a possible role of transporter deficiencies in susceptibility for colon carcinoma.