Is de novo hepatocellular carcinoma after transjugular intrahepatic portosystemic shunt increased?

BACKGROUND: Portal hypertension is a major complication of liver cirrhosis. Transjugular intrahepatic portosystemic shunt is effective in treatment of portal hypertension. However, decreased parenchymal portal venous flow after transjugular intrahepatic portosystemic shunt insertion favours ischaemic liver injury which has been discussed to induce hepatocarcinogenesis causing hepatocellular cancer. AIM: This study aimed to explore the association between transjugular intrahepatic portosystemic shunt placement and the development of hepatocellular cancer. METHODS: A total of 1338 consecutive liver cirrhosis patients were included in this retrospective study between January 2004-December 2015. Data were analysed with regard to development of hepatocellular cancer during follow-up. Binary logistic regression and Kaplan-Meier analyses were conducted for the assessment of risk factors for hepatocellular cancer development. In a second step, to rule out confounders of group heterogeneity, case-control matching was performed based on gender, age, model of end-stage liver disease score and underlying cause of cirrhosis (non-alcoholic steatohepatitis, alcoholic liver disease and viral hepatitis). RESULTS: Besides established risk factors such as older age, male gender and underlying viral hepatitis, statistical analysis revealed the absence of transjugular intrahepatic portosystemic shunt insertion as a risk factor for hepatocellular cancer development. Furthermore, matched-pair analysis of 432 patients showed a significant difference (p = 0.003) in the emergence of hepatocellular cancer regarding transjugular intrahepatic portosystemic shunt placement versus the non-transjugular intrahepatic portosystemic shunt cohort. CONCLUSION: In patients with end-stage liver disease, transjugular intrahepatic portosystemic shunt insertion is significantly associated with reduced rates of hepatocellular cancer development.

Colon capsule endoscopy versus standard colonoscopy in assessing disease activity of ulcerative colitis: a prospective trial.

BACKGROUND: The aim of our study was to compare colon capsule endoscopy (CCE) with standard colonoscopy (SC) in the assessment of mucosal disease activity and localization of inflammatory colonic mucosa in patients with known ulcerative colitis (UC). METHODS: Thirteen symptomatic patients (8 males, 5 females, mean age 38.5 ± 12.0 years) with known UC (mean duration of colitis: 9.7 ± 8.1 years) and indication for endoscopy due to suspected disease activity were included. All patients underwent CCE (first generation capsule, Given Imaging Ltd., Yokneam, Israel) on day 1 followed by SC on day 2 in a single center non-randomized, non-placebo-controlled diagnostic study (NCT00837304). SC and CCE were video recorded, and analysis was independently performed by 6 experienced endoscopists. The modified Rachmilewitz score was calculated, and Wilcoxon signed-rank test was used for analysis. Difference in recognition of disease activity by the endoscopists was assessed by application of the Kruskal-Wallis test. RESULTS: Assessment of disease activity revealed a significantly higher Rachmilewitz score of 7.3 ± 2.9 in the SC group compared to 4.8 ± 3.4 in the CCE group. Significantly, more detection of vessel vulnerability, granulated mucosa and mucosal damage was seen by SC. Disease extension was underestimated by CCE compared to SC. Disease activity assessment by means of SC or CCE did not differ statistically between the investigators (p = 0.26 and p = 0.1, respectively). After CCE, the capsule egestion rate was 77 %. The overall acceptance of both procedures was similar. CONCLUSION: Considering the significantly different assessment of disease activity and significantly more appropriate assignment of the horizontal spread of inflammation by SC versus CCE, we recommend the preferential use of SC in the assessment of inflammation in UC patients.

Single- vs. double-balloon enteroscopy in small-bowel diagnostics: a randomized multicenter trial.

BACKGROUND AND STUDY AIMS: Double-balloon enteroscopy (DBE) is the first choice endoscopic technique for small-bowel visualization. However, preparation and handling of the double-balloon enteroscope is complex. Recently, a single-balloon enteroscopy (SBE) system has been introduced as being a simplified, less-complex balloon-assisted enteroscopy system. PATIENTS AND METHODS: This study was a randomized international multicenter trial comparing two balloon-assisted enteroscopy systems: DBE vs. SBE. Consecutive patients referred for balloon-assisted enteroscopy were randomized to either DBE or SBE. Patients were blinded with regard to the type of instrument used. The primary study outcome was oral insertion depth. Secondary outcomes included complete small-bowel visualization, anal insertion depth, patient discomfort, and adverse events. Patient discomfort during and after the procedure was scored using a visual analog scale. RESULTS: A total of 130 patients were included over 12 months: 65 with DBE and 65 with the SBE technique. Patient and procedure characteristics were comparable between the two groups. Mean oral intubation depth was 253 cm with DBE and 258 cm with SBE, showing noninferiority of SBE vs. DBE. Complete visualization of the small bowel was achieved in 18 % and 11 % of procedures in the DBE and SBE groups, respectively. Mean anal intubation depth was 107 cm in the DBE group and 118 cm in the SBE group. Diagnostic yield and mean pain scores during and after the procedures were similar in the two groups. No adverse events were observed during or after the examinations. CONCLUSIONS: This head-to-head comparison study shows that DBE and SBE have a comparable performance and diagnostic yield for evaluation of the small bowel.

Post-ERCP pancreatitis in 2364 ERCP procedures: is intraductal ultrasonography another risk factor?

BACKGROUND AND STUDY AIMS: Acute pancreatitis is considered a relevant major complication following endoscopic retrograde cholangiopancreatography (ERCP); according to literature data, the incidence varies between 1.5 % and 17 %. In the present study, we aimed to identify potentially new, hitherto unknown risk factors for post-ERCP pancreatitis. PATIENTS AND METHODS: A total of 2364 ERCP procedures performed in 1275 patients during the years 2004 - 2008 were included in the study. Post-ERCP pancreatitis was defined as acute abdominal pain within 48 hours following ERCP with at least 3-fold elevated levels of serum lipase and a requirement for analgesic drugs for at least 24 hours. The severity of the pancreatitis was determined using the Imrie score. RESULTS: In our cohort study a total of 54 different patients (2.3 %) developed post-ERCP pancreatitis. In 50 of these patients (92.6 %) the pancreatitis was mild; in 54 (7.4 %) it was severe. Patients with post-ERCP pancreatitis had highly significantly lower bilirubin levels than patients who did not have post-ERCP pancreatitis ( P < 0.001). Length of hospital stay, duration of analgesics, and need for analgesic drugs were significantly higher in patients suffering from severe pancreatitis ( P ≤ 0.01). In multivariate analysis, among other, already well-described risk factors we identified intraductal ultrasonography as another risk factor for post-ERCP pancreatitis, with a hazard ratio of 2.41 ( P = 0.004). CONCLUSIONS: According to our retrospective data, intraductal ultrasonography seems to be another independent risk factor for developing post-ERCP pancreatitis, which needs to be further elucidated in prospective studies.

Missorting of cathepsin B into the secretory compartment of CI-MPR/IGFII-deficient mice does not induce spontaneous trypsinogen activation but leads to enhanced trypsin activity during experimental pancreatitis--without affecting disease severity.

The lysosomal protease cathepsin B is thought to play a crucial role in the intracellular activation cascade of digestive proteases and in the initiation of acute pancreatitis. Although cathepsin B has been shown to be physiologically present in the secretory pathway of pancreatic acinar cells it has been suggested that premature activation of zymogens requires an additional redistribution of cathepsin B into the secretory compartment. Here, we studied the role of cathepsin B targeting during caerulein-induced pancreatitis in mouse mutants lacking the cation-independent mannose 6-phosphate/insulin-like growth factor II receptor (CI-MPR) which normally mediates the trafficking of cathepsin B to lysosomes. Absence of the CI-MPR led to redistribution of cathepsin B to the zymogen granule enriched subcellular fraction and to a substantial formation of large cytoplasmic vacuoles that contained both, trypsinogen and cathepsin B. However, this did not cause premature intracellular trypsin activation in saline-treated control animals lacking the CI-MPR. During caerulein-induced pancreatitis, trypsinogen activation in the pancreas of CI-MPR-deficient animals was about 40% higher than in wild-type animals but serum amylase levels were reduced and lung damage was unchanged. These data suggest that subcellular redistribution of cathepsin B, in itself, induces neither spontaneous trypsinogen activation nor pancreatitis. Furthermore, we clearly show that a marked increase in intracellular trypsinogen activation is not necessarily associated with greater disease severity.

CCR6 identifies lymphoid tissue inducer cells within cryptopatches.

The chemokine receptor CCR6 is expressed by dendritic cells, B and T cells predominantly within the organized structures of the gut-associated lymphatic tissue. Its ligand CCL20 is synthesized by the follicle-associated epithelium and is crucial for the development of M cells within Peyer's patches. In addition, lineage-negative c-kit positive lymphocytes within cryptopatches (CP) express CCR6. CCR6-deficient mice exhibit an altered intestinal immune system containing increased amounts of intraepithelial lymphocytes and show smaller Peyer's patches, while progression of cryptopatches to mature isolated lymphoid follicles (ILF) is inhibited. In this report, we show that lin(-) c-kit(+) lymphocytes express a variety of different chemokine receptors and that CCR6 identifies those cells located within CP. In contrast, cells found outside CP are positive for CXCR3 and exhibit a different surface marker profile, suggesting that at least two different populations of lin(-) c-kit(+) cells are present. The presence of CCR6 does not influence the expression of Notch molecules on lin(-) c-kit(+) cells, nor does it influence Notch ligand expression on bone marrow-derived dendritic cells. In the human gut, CCR6 identifies clusters of lymphocytes resembling murine CP. CCR6 seems to have an important role for lin(-) c-kit(+) cells inside CP, is expressed in a regulated manner and identifies potential human CP.

[Leg ulcer in mixed connective tissue disease. Resolution during sitaxsentan therapy]. / Unterschenkelulzera bei Sharp-Syndrom. Abheilung unter Sitaxentan.

Leg ulcers may result in serious morbidity in patients with connective tissue diseases and Raynaud's phenomenon (RP). We describe a 35-year-old woman with mixed connective tissue disease who suffered from leg ulcers refractory to iloprost. When the patient was treated with the selective endothelin A receptor antagonist sitaxsentan for pulmonary arterial hypertension, the ulcers improved within 4 weeks and resolved completely thereafter. In addition, severity of RP ameliorated markedly. Further evaluation of sitaxsentan in patients with connective tissue diseases suffering from ischemic skin ulcers is required.

[Epidemiology of obesity]. / Epidemiologie der Adipositas.

Decades of obesity research have yielded no generally accepted strategy for safe and lasting weight loss. In spite of the importance given to it, obesity seems to be spreading like a virus. Is there really an epidemic of obesity? This survey looks at studies of the last 10 years from Germany, Europe, and worldwide and compares them with older data.Currently 32.9% of US adults and 13% of US children are obese; in Europe 15.7% of adults are obese and 4% of children and adolescents; in Germany 22.9% of adults are obese, while the figure is 6.3% for children and adolescents. Obviously there are characteristic differences in the worldwide distribution: obesity is more prevalent among women and also in lower social classes or among migrants. Every seventh non-Hispanic black woman in the US has a body mass index of over 40 kg/m(2) (morbid obesity). Obesity is increasing worldwide, especially among children. Morbid obesity is growing twice as fast as diabetes mellitus prevalence and will overtake it.In summary, obesity has developed from a secondary issue to a major national and international epidemic. In the near future, costs of prevention and treatment of obesity and its complications can no longer be covered by the health system. This explains why obesity is politically not recognized as a chronic illness.

[Gastroenterological palliative care]. / Gastroenterologische Palliativmedizin.

On consideration of current medical and socio-economical factors, palliative care is becoming an increasingly important aspect of modern medicine in Germany. The German Society for Digestive and Metabolic Disorders (DGVS) has taken this into account by founding the working group "Palliative Gastroenterology". Patients with gastrointestinal malignancies or advanced non-malignant liver disease represent an important group that benefits from palliative care. Approximately 80 % of all palliative care patients suffer from gastrointestinal symptoms and endoscopic procedures performed by gastroenterologists play an important role in relieving symptoms such as obstruction. It is the object of this paper to evaluate the role of gastroenterologists in palliative medicine. It will give a brief definition, a historical review and the current legal background for palliative care in Germany and examine special aspects of ethics, decision making and research. Considering the current evidence on palliative endoscopic procedures this paper wants to establish the role of the gastroenterologist in palliative care far beyond the mere practicalities of endoscopy. The gastroenterologist is a crucial element of the interdisciplinary palliative care team and a partner to the patient in the process of decision-making. Finally, it is demonstrated how palliative care structures can be implemented in the setting of a university acute-care hospital.

The role of interleukin-10 promoter polymorphisms in primary Sjogren's syndrome.

OBJECTIVE: To determine the impact of a broad spectrum of different polymorphisms within the interleukin-10 (IL-10) promoter gene on disease susceptibility to primary Sjogren's syndrome (pSS), clinical manifestations, and autoantibody production. METHODS: We genotyped 111 unrelated German Caucasian patients with pSS and 145 healthy controls for the single nucleotide polymorphisms (SNPs) at positions -2849, -2776, -2769, -2763, -1349, -1082, -851, -819, -657, and -592 and for the microsatellites IL10.R and IL10.G. Allele and haplotype distributions were compared between patients and controls and between subgroups of patients with different clinical and laboratory findings. RESULTS: We found no significant differences in the allele or haplotype frequencies between pSS patients and healthy controls. After Bonferroni correction we found a significant association of the ACC haplotype (at the -1082, -819, and -592 loci) with immunoglobulin (Ig)A antibodies to anti-alpha-fodrin. CONCLUSION: Overall we found no associations of IL-10 promoter polymorphisms with the susceptibility to pSS in our cohort. The finding that the production of IgA anti-alpha-fodrin antibodies is associated with polymorphisms within the IL-10 promoter region suggests a genetic contribution to the generation of these antibodies.

A novel A121T mutation in human cationic trypsinogen associated with hereditary pancreatitis: functional data indicating a loss-of-function mutation influencing the R122 trypsin cleavage site.

BACKGROUND: The understanding of genetic risk factors for chronic pancreatitis increased in the last decade with the discovery of mutations in the cationic trypsinogen gene (PRSS1). The first mutation was detected at the R122 autocleavage site of the protein (R122H) and subsequently two other mutations in this region, R122C and V123M, were described that resulted in a similar phenotype of hereditary pancreatitis. This study reports a novel A121T mutation within this region and characterises the resulting molecular properties at the autocleavage site. METHODS: Blood samples of a PRSS1 A121T carrier family were analysed for PRSS1 mutations using melting point curve analysis, restriction endonucleases and DNA sequencing. Conformation dependent properties of the mutated sequence were analysed by molecular modelling. The autodegradation kinetic of the mutated trypsin sequence was measured by a novel fluorescence resonance energy transfer (FRET) assay using designed 11 amino acid peptides from PRSS1 aa 118-aa 127 containing the trypsin cleavage site at aa 122 coupled to a Dabcyl/EDANS FRET system. The kinetic of tryptic peptide cleavage was measured in a fluorescence enzyme linked immunosorbent assay (ELISA) reader. RESULTS: DNA sequencing revealed a novel G to A transition at position 133279 of the published genomic sequence (#U66061 GenBank). The mutation results in an amino acid substitution of alanine by threonine at position 121 (A121T) of the cationic trypsinogen. Four additional mutation carriers could be identified among the relatives while only the first patient developed chronic pancreatitis. Molecular modelling of PRSS1 A121T revealed a change in the bond pattern between the R122 region and the calcium binding loop, whereas FRET assays showed an increased trypsin cleavage rate with a reaction kinetic elevated by more than 80%. CONCLUSION: The novel PRSS1 A121T mutation highlights the surface exposed region PRSS1 A121-R122-V123 as a hotspot for hereditary pancreatitis associated trypsinogen mutations. Molecular modelling and FRET assays provide evidence for an A121T mutation dependent increase in susceptibility to trypsin digestion at the R122 cleavage site suggesting an enhanced autodegradation and a loss-of-function at the autocleavage site.

CD4+ T cells transfer resistance against Citrobacter rodentium-induced infectious colitis by induction of Th 1 immunity.

Citrobacter rodentium induces an acute, self-limited colitis in mice which is histologically associated with crypt hyperplasia. The infection serves as a model for human infectious colitis induced by enteropathogenic Escherichia coli. We investigated if Balb/c mice, which had spontaneously cleared C. rodentium infection, were protected against re-infection and if resistance against intestinal infection can be systemically transferred using spleen cells. The course of infection was monitored by faecal excretion. Spleen cells, splenic CD3+ and CD4+ cells were transferred from resistant mice to non-infected recipients prior to infection. Cytokine secretion, serum and faecal antibody titres and histological disease severity were assessed. Balb/c mice were resistant against re-infection. The course of infection was shorter in mice receiving primed spleen cells, CD3+ and CD4+ cells. Transfer of CD4+ T cells from resistant mice induced gamma-interferon, interleukin (IL)-2 and IL-17 secretion and suppressed IL-10 secretion. Anti-Citrobacter serum IgG1 and IgG2a enzyme-linked immunosorbent assay OD levels were increased. Faecal IgA secretion was increased while serum IgA was suppressed in recipients of CD4+ cells. Large bowel histology showed protection from colitis in recipients of primed cells as indicated by normal colonic epithelium. In Balb/c mice, C. rodentium infection is followed by resistance, which can be transferred by CD4+ cells. Transfer of protection is associated with IL-17 secretion, enhanced serum IgG and faecal IgA secretion. This is the first study to demonstrate the mechanisms by which systemic resistance from previously C. rodentium-infected mice can be transferred to non-infected animals.

Carbon dioxide insufflation improves intubation depth in double-balloon enteroscopy: a randomized, controlled, double-blind trial.

BACKGROUND AND STUDY AIMS: Double-balloon enteroscopy (DBE) has been proven effective for deep intubation of the small bowel. However, intubation depth is limited by distention of the small bowel due to air insufflation during the procedure. The present trial investigated whether carbon dioxide (CO (2)) instead of standard air insufflation would improve intubation depth during DBE, as well as reduce postprocedure pain. PATIENTS AND METHODS: One hundred and twelve consecutive patients scheduled for DBE at two centers were randomly assigned to either CO (2) or air insufflation during DBE. Patients and endoscopists were blinded with regard to the type of gas used. Intubation depth was registered using a validated form. Patients scored pain and discomfort during and after the examination on a 100-mm visual analog scale. RESULTS: One hundred patients were eligible for data analysis (48 in the CO (2) group and 52 in the air group). The mean small-bowel intubation depth was extended by 30 % in the CO (2) group compared to the air group (230 vs. 177 cm, P = 0.008). The superiority was most pronounced for oral DBE, with a 71-cm improvement in intubation depth when using CO (2) (295 cm in the CO (2) group vs. 224 cm in the air group, P < 0.001). Patient pain and discomfort were significantly reduced in the CO (2) group at 1 and 3 hours after the examination. CONCLUSIONS: CO (2) insufflation significantly extended intubation depth in DBE. CO (2) insufflation also reduces patient discomfort. CO (2) insufflation may lead to a higher diagnostic and therapeutic yield of DBE, with reduced patient discomfort.

Clinical and immunological characteristics of patients with Sjögren's syndrome in relation to alpha-fodrin antibodies.

OBJECTIVES: To analyse the prevalence of alpha-fodrin antibodies in patients with primary (pSS) and secondary Sjögren's syndrome (sSS) and the relation to clinical, serological and immunological features. METHODS: Serum IgA and IgG antibodies to the 120 kDa alpha-fodrin were determined by ELISA technique in 62 pSS patients and 28 sSS patients. Results were correlated with clinical symptoms and laboratory findings as well as with the HLA-DR genotype. Additionally, antibody concentrations were correlated with the numbers of peripheral blood mononuclear cells (PBMCs) secreting interleukin (IL)-6, IL-10, interferon-gamma (INF)-gamma, and tumour necrosis factor-alpha determined by ELISPOT analysis. Lymphocytes and monocytes were examined flow-cytometrically for the expression of activation markers. Healthy age- and sex-matched volunteers served as controls. RESULTS: The sensitivity of IgA and IgG alpha-fodrin antibodies was 35 and 31%, respectively, in pSS patients. In sSS patients, the sensitivity was 29 and 21%, respectively. In pSS patients with IgG antibodies, recurrent parotid swelling was significantly more prevalent. Also the number of INF-gamma secreting PBMCs and the percentage of CD4/CD71+ lymphocytes as well as CD14/HLA-DR+ monocytes were significantly increased in this group compared with alpha-fodrin-negative patients or with controls. Interestingly, these patients also had a shorter disease duration. No association of alpha-fodrin antibodies with the HLA-DR genotype was found. CONCLUSION: Due to the low prevalence, serum antibodies to alpha-fodrin turned out to be of limited diagnostic value in our study. However, our data suggest that IgG antibodies to alpha-fodrin are indicative of clinical and immunological activity in pSS especially in patients with shorter disease duration and may thus serve as a marker of disease activity.