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Felix Stickel and colleagues report the results of a genome-wide association study of alcohol-related cirrhosis. They confirm PNPLA3 as a susceptibility locus and identify new association signals in MBOAT7 and TM6SF2 . Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world 1 , 2 , 3 . We performed a genome-wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 ( P = 1.03 × 10 −9 ) and TM6SF2 ( P = 7.89 × 10 −10 ) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis ( P = 1.54 × 10 −48 ) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.

Background: Crohn’s disease (CD) and ulcerative colitis (UC) commonly affect women in their childbearing years. Vedolizumab (VDZ) is approved for treatment of moderate-to-severe CD and UC, but there is a knowledge gap regarding its use during pregnancy. This targeted literature review describes available evidence on safety of VDZ in pregnant patients in order to offer physicians a detailed and balanced view on persistent data during their decision-making process for an individualized treatment concept. Methods: The search included literature from the MEDLINE database and abstracts of five gastroenterological conferences published until November 2019. Publications were included if pregnancy outcomes in women receiving VDZ or neonatal outcomes in newborns of women previously exposed to VDZ were reported. Results: Out of 196 initially identified records, 18 publications reporting results of five different studies were identified. In total, for 213 of 284 VDZ-exposed documented pregnancies the following pregnancy outcomes were reported: 167 live births (172 infants due to twin births), 1 stillbirth, 35 miscarriages, 10 elective terminations (1 due to detected Down syndrome). Furthermore, during pregnancy, the following complications were observed: seven cases of (pre) eclampsia, three cases of premature rupture of membranes and one case each of placenta previa, chorioamnionitis, pneumonia, first-trimester bleeding, cholestasis, sepsis, or neonatal intraventricular hemorrhage. Based on 172 infants, 30 preterm deliveries (17.4%), 9 cases of low birth weight (5.2%), 5 infections (2.9%), and 6 cases (3.8%) with congenital anomalies were reported. Conclusion: There was no evidence for safety concerns regarding pregnancy outcomes associated with VDZ therapy. Due to the limited scope of included records, further research is needed to understand the safety profile regarding the use of VDZ during pregnancy.

ObjectivePerianal fistulas in Crohn’s disease (CD) are associated with a high burden of illness and their treatment is challenging. Recent data indicate promising short-term efficacy of bone marrow-derived mesenchymal stromal cell (bmMSC) therapy. The aim of this case series is to gather more information on the long-term effectiveness and safety.MethodsBetween 2013 and 2017, bmMSCs were administered under compassionate use to patients at a university hospital in Germany, as no stem cell therapy was approved at the time. Inclusion criteria were inactive CD (Harvey-Bradshaw Index <5) without proctitis, at least one treatment-refractory perianal fistula (with or without rectovaginal additional fistulas) and prior tumour necrosis factor-alpha inhibitor and/or surgical exposure. After curettage of the fistula tract, patients received repeated intrafistular injections with up to 300 million bmMSCs. We retrospectively analysed patient records to assess disease course, clinical fistula remission and radiological activity using the modified van Assche index.ResultsSix female patients with a total of 13 fistulas (9 trans-sphincteric, 2 extrasphincteric and 2 rectovaginal) underwent bmMSC application. Median radiological and clinical long-term follow-up was 80 months (range 44–98 months) after first local bmMSC injection. 8 of 13 fistulas (62%) exhibited complete closure. For rectovaginal fistulas, long-term remission (98 months) was 50% (1 of 2). Pelvic MRI showed a decrease in modified Van Assche index from baseline to long-term follow-up. No immediate adverse events related to bmMSC injections were observed. One patient was diagnosed with a local adenocarcinoma of the rectum 106 months after first bmMSC injection. MRI control 11 months prior showed complete fistula remission. The tumour exhibited a female karyotype, while bmMSC had been derived from a male volunteer.ConclusionIn this analysis, 62% of complex perianal and 50% of rectovaginal fistulas showed long-term remission up to 8 years post–bmMSC therapy. Further real-world data are needed.

BackgroundIn Helicobacter pylori (H. pylori) positive stage I gastric low-grade MALT lymphoma, eradication is the accepted first-line therapy. The role of eradication therapy in lymphoma > stage IE is still unclear. However, about 20% of patients show persistent lymphoma following successful eradication or primary H. pylori-negative lymphoma. A prospective study for salvage radiation therapy with standard 36 Gy in comparison to a reduced dose of 25.2 Gy is still missing.MethodsA prospective, multicentre study investigated the efficacy of eradication in H. pylori-positive gastric low-grade MALT lymphoma stages IE and II1E (HELYX I). Refractory lymphoma or H. pylori-negative patients were treated in a prospective, randomised, multicentre, phase II study to receive either 25.2 Gy or 36 Gy radiotherapy (HELYX II).Results102 patients (3 drop outs) were included in HELYX I: 75/99 (75.8%) showed complete remission after a median of 2.8 months. 18 (18.2%) had partial remission (PR) and 6 (6.0%) no change (NC). 29 patients (7 drop outs) were randomized in HELYX II (7 primarily H. pylori-negative, 15 patients from HELYX I with refractory disease after eradication). All patients achieved stable CR irrespective of radiation dose. Both presence of the t(11,18) translocation (OR 9.0, p = 0.01) and monoclonality of the tumour cells (OR 6.3, p = 0.006) were predictors for persistant lymphoma after eradication therapy.ConclusionsMost H. pylori-positive low grade gastric MALT lymphoma stage IE and II1E respond with stable CR after eradication therapy. In patients with refractory disease or H. pylori negative low grade gastric MALT lymphoma a dosage-reduced radiation therapy with 25.2 Gy is an effective standard dose in stage IE and II1E.Trial registrationClinicalTrials.gov: NCT00154440.

Clostridium difficile (CD) infection is the main cause of nosocomial enterocolitis in western countries and in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHCT). Recipients of alloHCT are at high risk for CD infection but large studies in this population are rare and conflicting results have been reported. We analyzed 727 patients with AML or MDS undergoing alloHCT in our center from 2004 to 2015. Ninety-six patients (13%) had CD infection and 103 patients (14%) were identified as asymptomatic carriers by screening at admission and once a week during aplasia. Patients with CD infection had a shorter median overall survival of 8 months (95% CI, 6–36 months) compared with 25 months (95% CI, 17–35 months) for patients without CD infection, (HR 1.4, p = 0.04). CD positive patients were less likely to develop acute graft-versus-host disease (aGvHD; HR 0.6, p = 0.004) compared with CD-negative patients, but did not show differences in gastrointestinal aGvHD (HR 0.9, p = 0.5). Symptomatic patients developed gastrointestinal aGvHD (HR 2.5, p = 0.02) more often compared with asymptomatic CD positive patients. This analysis demonstrates a high prevalence for CD infection in patients undergoing alloHCT. A significant lower overall survival for patients with CD infection could be demonstrated.

INTRODUCTION:Individuals with a family history (FH) of colorectal cancer (CRC) are at increased risk of CRC. We aimed to assess the objective role and subjective perception of risk factors of colorectal neoplasia within this high-risk group.METHODS:Questionnaire and screening colonoscopy results were obtained from individuals aged 40-54 years with a reported FH of CRC in a first-degree relative in a multicenter cross-sectional study in Germany. Descriptive statistics characterized the cohort and distribution of risk factors. Multivariable logistic regression was used to derive adjusted odds ratios (aORs) and corresponding 95% confidence intervals (CIs) to evaluate factors associated with colorectal neoplasia and with subjectively perceived increased CRC-risk.RESULTS:Among 922 participants, 220 (23.9%) were diagnosed with colorectal neoplasia, 63 (6.8%) of these being advanced lesions. Strong associations with advanced neoplasia were observed for obesity (aOR 2.44, 95% CI 1.12-5.22), smoking (aOR 1.47, 95% CI 1.14-1.88 per 10-pack-years) and physical activity <45 minutes per day (aOR 2.51, 95% CI 1.11-5.25). For smoking and physical activity, but not for obesity, similar associations were also seen with any colorectal neoplasia. No associations were seen with number and age at diagnosis of affected family members. By contrast, the latter factors, but none of the behavioral factors were strongly associated with subjectively perceived CRC-risk.DISCUSSION:Within a cohort of individuals aged 40-54 years with a FH of CRC, obesity, smoking, and lack of physical activity represented the most prominent modifiable risk factors for the development of advanced colorectal neoplasia but did not significantly impact risk perception in these high-risk participants.

We report on a patient with Crohn’s disease who developed an extensive Mycobacterium marinum infection under combined immunosuppression. M. marinum infection was initially neither considered nor screened for, leading to considerable disease progression. We believe this patient report helps to raise awareness of a rare but important opportunistic infection.

Background and Aims Pyoderma gangrenosum (PG) is a rare but challenging extraintestinal manifestation (EIM) of inflammatory bowel disease (IBD), affecting 6–48% of IBD patients. This retrospective study analyzes affected patients and evaluates therapeutic strategies for both IBD remission and PG resolution. METHODS A multicenter retrospective analysis was conducted on patients with IBD and PG in 8 tertiary centers in Germany and Austria. Demographic data, prior therapies, surgeries, treatment of PG were collected, and treatment responses assessed. RESULTS The cohort included 50 patients (median age: 43 years; 68% female). Crohn’s disease (CD) was present in 58%, ulcerative colitis (UC) in 42%. Fifty percent of patients had prior surgery, 68% having an intestinal stoma. 48% were experienced to biologic therapy, predominantly anti-TNF therapy (83%). PG mainly affected the lower extremities (52%) and peristomal areas (24%). Systemic steroids were used in 52% of patients and led to PG resolution in only 12%. Anti-TNF therapy was the main approach, used in 68% of patients, with resolution achieved in 80%. Calcineurin inhibitors were given to 26% of patients and induced resolution in 38%. Three of six non-responders were successfully switched to infliximab. Overall PG resolution was achieved in 80%, correlating with IBD remission in 78%. The median time to PG resolution was five months. CONCLUSION Anti-TNF therapy was an effective treatment for PG in IBD patients, even in those with prior non-response to calcineurin inhibitors. Systemic steroids showed low response rates. PG healing mostly aligned with IBD remission, underlining the need for tailored long-term therapy.

Purpose: Decreased olfactory and gustatory functions are present in various systemic autoimmune diseases. However, little is known about the chemosensory functions of patients with inflammatory bowel disease (IBD). The present study aimed to investigate olfactory and gustatory functions in patients with IBD and their correlation with clinical disease activity. Methods: A total of 103 patients with IBD were included (52 men, 51 women, mean age 40.3 ± 1.2 years) in the present study. Chemosensory functions were assessed utilizing the “Sniffin’ Sticks” olfactory function test and “taste sprays” gustatory function test. The clinical disease activity of patients was graded as remission, mild, and moderate–severe. In addition, inflammatory markers (fecal calprotectin, C-reactive protein and blood leucocyte count) were recorded. Results: In total, 70% of IBD patients were normosmic, 30% were hyposmic, and none of them was functionally anosmic; 6% of the patients showed signs of hypogeusia. Patients with moderate–severe IBD reached a higher olfactory threshold score compared with patients with remission (p = 0.011) and mild IBD (p < 0.001). The BMI of IBD patients was inversely correlated with their olfactory threshold (r = −0.25, p = 0.010). Olfactory and gustatory function in IBD patients did not correlate with duration of disease, blood leucocyte count, CRP level, or fecal calprotectin level. However, patients’ olfactory function significantly increased after 4 months of TNF-α inhibitor treatment (p = 0.038). Conclusions: IBD patients are more likely to present with hyposmia. Olfactory thresholds were mainly affected. They were significantly associated with clinical disease activity and BMI. As shown in a subgroup, treatment with TNF-α inhibitors appeared to improve olfactory function.

ObjectiveHomozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants (‘Pi*Z’ and ‘Pi*S’), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse.DesignWe analysed multicentric case–control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed.ResultsThe Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)).ConclusionThe Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%–4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.