Significance and clinical impact of routinely tested urinary ethyl glucuronide after liver transplantation - development of a risk score.

Alcohol abuse after liver transplantation can seriously impact graft and patient survival. However, to date, there is no defined standard procedure to identify patients consuming alcohol after liver transplantation. The aim of this study was to analyze the diagnostic value and clinical impact of routinely measured urinary ethyl glucuronide (uEtG) - a metabolite of ethanol - in patients after liver transplantation. Data of 362 consecutive patients after liver transplantation who visited the University Hospital of Tuebingen for outpatient follow-up were analyzed. Forty-eight patients (13%) displayed positive uEtG results. The uEtG positive group contained significantly more patients with pretransplant alcoholic liver disease. However, two thirds of the uEtG positive patients had no history of pretransplant alcoholic liver disease. Several clinical parameters were significantly associated with positive uEtG. In order to enable a more cost-effective application of uEtG in the future, a clinical risk score was developed (specificity 0.95). In conclusion, routine testing for uEtG reveals a considerable percentage of patients practicing alcohol intake after liver transplantation. Application of our proposed risk score could help focusing uEtG testing on patients at risk.

Infodemiology of Crohn's disease and Ulcerative colitis using Google Trends - an approach to investigate patient needs.

INTRODUCTION: Inflammatory bowel diseases (IBD) highly affect quality of life. The course of disease and success of treatment are variable. These factors result in a high number of psychiatric comorbidities with patients requiring extensive medical consultation or additional psychotherapy. Unfortunately, time is often limited in daily clinical care, which leaves patients not feeling sufficiently informed about their disease. Patients often compensate by searching the internet, with possibly harmful information. We aim to identify information gaps to allow a more complete education of patients. METHODS: We analyzed the internet search behavior using the key words [Morbus Crohn] (CD) and [Colitis ulcerosa] (UC) using Google Trends. In addition, we investigated which websites are the first hits on Google, as those are most likely visited by patients. RESULTS: Symptoms, nutrition and therapy are central topics for persons interested in IBD. The searches concerning symptoms or therapies do not match the actual incidence or prevalence of comorbidities as well as the more commonly used therapies or established nutritional recommendations. We found a distinct impact of well-known personalities on disease related searches. The first suggested websites on google showed great heterogeneity of responsible publishers, often with possible conflict of interests. In line with those observations, quality of website content is highly heterogeneous. CONCLUSION: This study showed a need of information concerning symptoms, nutrition and therapy that should be considered during patient education. Since time in physician patient dialogue is short it may be helpful to further evaluate websites independently in order to give recommendations of websites offering reliable information.

Ustekinumab serum concentrations are associated with clinical outcomes in Crohn's disease - a regional multi-center pilot study.

BACKGROUND AND AIM: The role of therapeutic drug monitoring (TDM) in ustekinumab (UST) therapy for Crohn's disease (CD) has not been established, as only few studies have analyzed the relationship between UST serum concentrations and clinical outcome. In this pilot study, we retrospectively examined the potential of UST-concentrations (cUST) 8 weeks after induction (cUSTw8) to predict clinical response at week 16. METHODS: Serum samples and clinical data from patients (n = 72) with moderate to severely active CD who received intravenous induction with UST were retrospectively analyzed. cUST were quantitated using liquid chromatography-tandem mass spectrometry (LC-MSMS). A receiver-operating characteristic (ROC) curve and area under ROC curve (AUROC) was computed to analyze the predictive potential of cUSTw8 for clinical response at week 16 and to determine the minimal therapeutic UST trough concentration. RESULTS: Forty-four patients (61 %) achieved clinical response to UST therapy at week 16. cUSTw8 was moderately effective to predict clinical response with a minimal therapeutic cUSTw8 of 2.0 mg/l (AUC 0.72, p = 0.001). CONCLUSION: Trough concentrations of UST 8 weeks after induction predict clinical response to therapy in week 16 with moderate sensitivity and specificity. TDM using LC-MSMS could prove beneficial in personalized UST therapy of patients with CD by identifying individuals with subtherapeutic concentrations who might benefit from dose escalation.

Enterocutaneous fistula in severely active Crohn's disease: preoperative anti-TNF alpha treatment to limit bowel resection-report of a case.

PURPOSE: Strategies for limiting the extent of bowel resection in cases of enterocutaneous or interenteric fistulas in severely active Crohn's disease are urgently necessary. Anti-inflammatory therapy with tumor necrosis factor alpha (anti-TNF alpha) inhibitors has positive impact on fistulizing Crohn's disease. We describe a case of a 32-year-old male suffering from enterocutaneous fistula in severely active Crohn's disease. METHODS: The patient's clinical course and data of therapy monitoring before bowel resection were reviewed and compared to the pretherapeutic findings. In addition, the reports of surgery and histopathological workup were evaluated and a clinical follow-up was performed. The literature on anti-TNF alpha treatment in fistulizing Crohn's disease was surveyed. RESULTS: A 32-year-old male with an 8-year history of Crohn's disease and condition after previous ileocecal and sigmoid resection at the age of 28 presented with increasing pain in the middle-right abdomen. Laboratory and radiologic assessment detected elevated C-reactive protein and presence of a conglomerate of inflammatory thickened and narrowed small intestine involving the neoterminal ileum and enteroenteric fistulas. Ileocolonoscopy showed a stenosing inflammation of the neoterminal ileum. After initial anti-infective therapy, as a result of an interdisciplinary decision, preoperative anti-TNF alpha treatment was performed to achieve limited bowel resection. After declining of inflammation, limited bowel resection was carried out successfully. CONCLUSIONS: Preoperative therapy with anti-TNF alpha might potentially reduce inflammation to subsequently limit the extent of bowel resection in selected cases of enterocutaneous or interenteric fistulas in severely active Crohn's disease. We describe an impressive case in which such therapeutic approach was carried out.

Low-grade appendiceal mucinous neoplasm (LAMN) - 3-year endoscopic follow-up underlines benign course of LAMN type 1.

Low-grade appendiceal mucinous neoplasms (LAMNs) are neoplastic lesions with potential progression to pseudomyxoma peritonei (PMP). In most cases, diagnosis is made because of suspected acute appendicitis or incidentally by computed tomography (CT). However, incidental diagnosis during colonoscopy is rare. We present the case of a 63-year-old man with a LAMN type 1 lesion, diagnosed at routine colonoscopy for surveillance of ulcerative colitis. Because in earlier surveillance colonoscopies, this lesion was misinterpreted as fecal polution, for the first time, this case describes retrospectively a 3-year endoscopic follow-up of LAMN type 1, underlining the benign course of these kind of lesions compared to type 2 lesions with submucosal infiltration. Even though endoscopy and sonography are not accepted as method of choice to detect LAMN lesions, our case highlights their role regarding diagnosis of small lesions, as CT scan was not able to detect the lesion in our case. Even though LAMNs are rare, awareness of LAMN lesions in routine colonoscopy is favorable as potential progression to PMP can not be ruled out.

Are Internet Information Sources Helpful for Adult Crohn's Disease Patients Regarding Nutritional Advice?

Background: Adult patients suffering from Crohn's disease (CD) are often dissatisfied with the information they receive from their physicians about nutrition and its impact on CD inflammation activity. Only a few publications are available about patients' internet research on nutrition in CD. The study aim is to elucidate the internet information sources of adult CD patients regarding nutritional advice via a questionnaire. Methods: A questionnaire with 28 (general and specific) questions for outpatients at our tertiary center with CD was created and used for an analysis of their information sources about nutrition in CD. Four CD and/or nutritional medicine experts examined the 21 most relevant websites referring to nutritional advice for CD patients. Results: One hundred and fifty CD patients reported their Internet research behavior for nutritional advice and their dietary habits. Many CD patients prefer to consult the Internet instead of asking their general practitioner (GP) for nutritional recommendations. Most of the websites providing nutritional advice for CD patients are of very poor quality and cannot be recommended. We found significant correlations between (a) nutritional habits of CD patients, (b) their information sources and several demographic or CD-related factors. There is a lack of websites which provide high-quality, good nutritional advice to CD patients. Conclusions: The majority of the examined websites did not provide sufficient information according to the CD guidelines and nutritional medicine guidelines. A higher quality level of website content (e.g., on social media or on university/center websites) provided by experienced physicians is required to secure trustworthy and reliable nutritional information in CD.

Improved tolerability by a modified intermittent treatment schedule of dasatinib for patients with chronic myeloid leukemia resistant or intolerant to imatinib.

Intermittent dosing of dasatinib with a once daily regimen has been shown to reduce side effects while preserving clinical efficacy in early and advanced phase chronic myeloid leukemia (CML). Yet, hematologic toxicity and fluid retention demand a dose modification or treatment discontinuation in selected patients. Patients resistant or intolerant to imatinib were retrospectively evaluated based on the toxicity-guided administration of a dose-reduced dasatinib regimen. Patients were treated with an on/off regimen (3 to 5 days on, 2 to 4 days off) to allow regression of dasatinib-dependent off-target toxicity. Patients were followed up by routine hematologic and cytogenetic assessment and molecular monitoring to safeguard clinical response to the altered drug schedule. Thirty-three CML patients primarily in chronic phase with imatinib intolerance (n = 11) or resistance (n = 22) were investigated. Nonexclusive reasons for dose reduction were hematologic toxicity (17/33, 51%) and pleural effusions (18/33, 55%). On/off treatment with a weekend drug holiday significantly reduced pleural effusions and hematologic toxicity. Eighteen of 31 (58%) patients showed effective disease control despite reduced total weekly dasatinib doses, either demonstrated by achieving an improved response level (12/31) or keeping the response level achieved by conventional continuous dosing (6/31). Of note, 10/12 patients with subsequently improved response have been treated for a minimum of 6 months with continuous dosing dasatinib regimens without having achieved the response level achieved after allowing drug holiday. Weekend treatment interruption of dasatinib allows continuation of dasatinib treatment for patients suffering from side effects. These data mandate prospective investigation of alternative intermittent targeting regimens.

Defective antibacterial barrier in inflammatory bowel disease.

The pathogenesis of inflammatory bowel disease (IBD) is very complex, including a variety of genetic and environmental contributing factors. In this context, over the past few years, a picture of IBD as a primary defect of the innate immune system rather than the adaptive immune system has evolved. The intestinal antimicrobial barrier morphologically consists of a single layer of epithelial cells and the mucus and constitutes the first defense mechanism against the microbial burden of the gut. From a more mechanistic point of view, this barrier additionally depends on a crucial interplay between the mucus and antimicrobial peptides like for instance defensins. Disturbances in this system are in the pathophysiological center stage of IBD genesis and progression. In this article we will give a short overview about some of the key mechanisms in this context with special attention on defensins and the mucus layer.

Chromoendoscopy in Combination with Random Biopsies for Patients with Pathogenic CDH1 Mutations Undergoing Endoscopic Surveillance.

OBJECTIVES: Germline mutations in the CDH1-gene are identified as the cause of 30-40% of cases of hereditary diffuse gastric cancer, an autosomal-dominant inherited cancer predisposition syndrome. Given this high risk of developing diffuse gastric cancer, carriers of a pathogenic CDH1 germline mutation are advised to undergo prophylactic gastrectomy. For patients preferring conservative management, endoscopic surveillance is recommended. The detection of diffuse gastric cancer using white light endoscopy, however, remains challenging. METHODS: Patients with pathogenic CDH1 mutation underwent (chromo)endoscopic surveillance or endoscopy prior to surgery. Biopsies were taken at suspicious sites identified by chromoendoscopy. In addition, endoscopically normal areas were assessed with mapping biopsies. Detection rates from endoscopic biopsies (mapping vs. targeted) and gastrectomy specimen were then compared. RESULT: Between 11/2015 and 12/2020, ten patients from four families with a known CDH1 germline mutation had a total of n = 24 endoscopies with n = 518 total biopsies being examined. Three patients were diagnosed with GC during the study period. These patients all had suspicious chromoendoscopic lesions (= detection rate 100%). In two of three patients who had suspicious chromoendoscopic lesions, signet cell carcinoma was also detected in mapping biopsies and multiple additional cancer foci were identified in the gastrectomy specimen. CONCLUSION: Chromoendoscopy facilitated detection of gastric carcinoma foci in CDH1 mutation carriers. Chromoendoscopy identified all patients with gastric cancer, but not all cancer foci present in these patients. We conclude that for patients opting against prophylactic total gastrectomy, the addition of chromoendoscopy to white light could be used to enhance diagnostic reliability of endoscopic surveillance.

Quality of life in inflammatory bowel diseases: it is not all about the bowel.

BACKGROUND/AIMS: The inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn's disease (CD) are chronic diseases mostly affecting young patients. As they are diseases accompanying patients for their entire life, and the quality of life (QUOL) interacts with disease activity, improving QUOL should be one of the main goals of therapy. This study aims to identify factors contributing to good or impaired QUOL. METHODS: Questionnaires addressing health-related QUOL and other psychological and social features were positioned on our institutions' webpage and on the webpage of the largest self-help group for IBD in Germany. Patients were subdivided according to their QUOL score with a cutoff of <60. We used the Short Inflammatory Bowel Disease Questionnaire, the Assessment of the Demand for Additional Psychological Treatment, and the Fear of Progression Questionnaire Short Form. RESULTS: High numbers of patients in both subgroups showed an impaired QUOL (87.34% in UC, 91.08% in CD). Active extraintestinal manifestations, smoking, high fear of progression and high demand for psychotherapy were associated with reduced QUOL. In addition, polypharmacological interventions did not result in a good QUOL, but ostomies are linked to improved QUOL especially in CD patients. CONCLUSIONS: Scores used in clinical day-to-day-practice mainly focusing on somatic factors do not sufficiently address important aspects concerning QUOL. Most importantly, extraintestinal manifestations show a hitherto underestimated impact on QUOL.

Platelets in chronic liver disease, from bench to bedside.

In the last decade, numerous studies revealed physiologic and pathophysiologic roles of platelets beyond haemostasis, a process to prevent and stop bleeding. These include the activation of the immune system and the promotion of inflammation, infection and cancer. Hence, the emerging view on the role of platelets has shifted - platelets are now seen as alert "sentinels" of the immune compartment, rather than passive bystanders. Herein, we review well-established and newly discovered features of platelets that define their natural role in maintaining blood haemostasis, but also their functional relationship with other cells of the immune system. We focus on recent studies underlining functional involvement of platelets in chronic liver diseases and cancer, as well as the effects of anti-platelet therapy in these contexts. Finally, we illustrate the potential of platelets as possible diagnostic and therapeutic tools in liver disease based on recently developed methodologies.

Ustekinumab is effective in biological refractory Crohn's disease patients-regardless of approval study selection criteria.

BACKGROUND/AIMS: Ustekinumab is effective in active Crohn's disease. In a retrospective study we assessed the clinical outcome in nonresponders to anti-tumor necrosis factor therapy, and/or conventional therapy and/or the α4ß7-integrin inhibitor vedolizumab. As approval study populations do not always reflect the average "real world" patient cohort, we assessed weather patients who would not have qualified for approval studies show similar outcomes. METHODS: Forty-one patients with mild to severe active Crohn's disease were treated with ustekinumab (intravenous 6 mg per kg/body weight) followed by subcutaneous ustekinumab (90 mg) at week 8. Depending on the clinical response maintenance therapy was chosen every 8 or 12 weeks. Clinical response was defined by Crohn's Disease Activity Index (CDAI) decline, decline of stool frequency or clinical improvement. Inclusion criteria for approval studies were assessed. RESULTS: The 58.5% (24/41) showed clinical response to ustekinumab. The 58.3% of this group (14/24) achieved clinical remission. Clinical response correlated significantly with drop of stool frequency and improvement of CDAI score. The 39 out of 41 patients had no side effects and we observed no serious infections. About a third of our patients would not have met ustekinumab approval study criteria. However, patients who did not meet study criteria showed clinical improvement numerically in the same range compared to patients who would have qualified for approval studies. CONCLUSIONS: Ustekinumab is effective, safe and well tolerated in a highly therapy refractory patient cohort. Even though a reasonable number of patients did not meet ustekinumab approval study criteria, approval study results seem to be representative to the overall patient cohort.

Tacrolimus Suppositories in Therapy-Resistant Ulcerative Proctitis.

BACKGROUND: Ulcerative proctitis may often be managed with topical salicylates or steroids alone, but in some patients, symptoms are persistent and severe. We analyzed the efficacy of tacrolimus suppositories in patients who had proven refractory to combined topical and systemic treatment. METHODS: In this retrospective analysis, ulcerative colitis activity index (CAI), side effects, co-medication and drug levels were assessed in 43 patients with distal ulcerative colitis who received suppositories containing 2 mg of tacrolimus b.i.d. as add-on medication. RESULTS: A total of 23 patients with ulcerative proctitis presented to follow-up within ≤50 days (mean 27.0 days) after suppositories were started. A decrease in CAI (from 8.0 to 5.5 points) was observed and 52.3% reached clinical remission (CAI ≤4). In total, 43 patients were available for analysis, of whom 9 had inflammation of the sigmoid colon as well. For the entire cohort, the median treatment duration was 76 days; 60% were in remission on the last documented visit. Serum measurements revealed a substantial tacrolimus level with a mean of 5.5 ng/mL. We observed one case of mild reversible acute kidney injury. CONCLUSIONS: In ulcerative proctitis, adding tacrolimus suppositories can be an effective and safe option when topical mesalazine, corticoid formulations and concomitant oral or parenteral medications have failed.

Human Endogenous Retroviruses: Residues of Ancient Times Are Differentially Expressed in Crohn's Disease.

BACKGROUND: Eight percent of the human genome consists of human endogenous retroviruses (HERV). These genetic elements are remnants of ancient retroviral germ-line infections. Altered HERV expression is associated with several chronic inflammatory diseases. A physiological role of the HERV-derived proteins syncytin-1 and -2 has been described for the integrity of the human placental cell layer in terms of maintaining feto-maternal tolerance. The aim of this project was to investigate HERV expression in Crohn's disease (CD) with a further focus on syncytins in the gut. MATERIAL AND METHODS: Seventy-four ileal and colonic tissue samples of CD patients and healthy controls have been investigated for mRNA expression of major HERV groups by a comprehensive microarray screening. The most prominent differences have been validated by qRT-PCR. Immunohistochemistry (IHC), Western Blot (WB) and qRT-PCR were performed for syncytin-1 and -2. RESULTS: HERV microarray screening revealed a distinct expression profile in ileal and colonic tissue, as well as differential expression in CD compared to healthy controls. qRT-PCR validated differential expression of at least 3 HERV-groups in CD. qRT-PCR, IHC and WB showed a tissue-dependent diminished epithelial expression of syncytins in inflamed CD. CONCLUSION: For the first time, HERV expression has been comprehensively studied in the gut. Between CD and healthy controls we could show a tissue dependent differential HERV expression profile. Notably, we could show that syncytin-1 and -2 are expressed in the epithelial layer in ileal and colonic tissue samples, whereas their diminished tissue-dependent expression in inflamed CD might modulate inflammatory processes at the gut barrier.

[Crohn's Disease - New Therapies]. / Chronisch entzündliche Darmerkrankungen: Neue Therapieformen.

New promising treatment options for chronic inflammatory bowel diseases, confirm the expanded pathophysiological understanding in terms of the interactions of the gastrointestinal microbiome with the adaptive and innate immune response and barrier protection. Therefore, these interrelations are focus of research and therapeutic strategies. The following review will give insights into the pathomechanisms, current treatment options and future developments.

Practical guidance for the management of iron deficiency in patients with inflammatory bowel disease.

Iron deficiency or iron deficiency anemia (IDA) are some of the most common systemic complications of inflammatory bowel diseases (IBD). Symptoms such as fatigue, reduced ability to concentrate and reduced exercise tolerance can mimic common symptoms of IBD and can therefore easily be overseen. Furthermore, clinicians tend to see mild to moderate anemia as an inevitable accompaniment of IBD that is sufficiently explained by the underlying disease and does not require further workup. But in contrast to these clinical routines, current guidelines recommend that any degree of anemia in patients with IBD should be further evaluated and treated. Multiple studies have shown that anemia is a main factor for decreased quality of life (QoL) in patients with IBD. Correction of anemia, however, can significantly improve the QoL of patients with IBD. It is therefore recommended that every patient with IBD is regularly screened for iron deficiency and anemia. If detected, appropriate workup and treatment should be initiated. Over the last years, a number of new diagnostic tools and treatment options have been developed. Multiple studies have demonstrated the safety of newer formulations of intravenous iron in patients with IBD and have compared oral and intravenous iron in various situations. Treatment recommendations have changed and new evidence-based guidelines were developed. However, to date these guidelines are still not widely implemented in clinical practice. The aim of this review is to draw attention to the need for treatment for every level of anemia in patients with IBD and to provide some practical guidance for screening, diagnostics, treatment and follow up of IDA in patients with IBD following current international guidelines.

GLP-2 analog teduglutide significantly reduces need for parenteral nutrition and stool frequency in a real-life setting.

BACKGROUND: To evaluate the benefits of teduglutide in a real-life setting, we analyzed the data of 14 patients with short bowel syndrome treated with teduglutide. Additionally, we studied glucagon-like peptide 2 (GLP-2) receptor expression in samples of small intestinal and colonic tissue to provide explanations for clinical observations. METHODS: Stool frequency and consistency, sensation of thirst, parental calorie or fluid uptake and the number of days on parenteral support per week were collected for up to 2 years. Quantitative real-time polymerase chain reaction of the GLP-2 receptor in healthy controls was performed to better understand clinical response in different patient subgroups. RESULTS: There was a significant reduction in parenteral support after 24 and 48 weeks (by 11.0 and 36.6%, respectively; p < 0.05). Further major improvements were made in several patients after over 1 year (reduction by 79.3%, p < 0.05). The proportion of patients who reduced parenteral support by at least 20% was 33.3%, 54.5% and 71.3% after 24 weeks, 48 weeks and beyond 1 year, respectively. Patients on daily parenteral support showed late but strong amelioration. The reduction of thirst was the earliest marker for response. While stool consistency increased (p < 0.01), stool frequency decreased (p < 0.05) significantly after 12 weeks. This reduction was even more pronounced in patients with colon in continuity. Supporting these clinical observations, we found a stronger physiological expression of the GLP-2 receptor in the colon than in the small intestine. CONCLUSIONS: Patients benefit from teduglutide in a real-life setting, but in contrast to randomized, controlled studies reduction of parenteral support took longer. We identified early clinical markers of response, such as stool consistency and frequency as well as sensation of thirst. Clinical and molecular observations support the role of the colon as an important target organ of teduglutide.

ß-Defensin 1 Is Prominent in the Liver and Induced During Cholestasis by Bilirubin and Bile Acids via Farnesoid X Receptor and Constitutive Androstane Receptor.

Background & aims: Knowledge about innate antimicrobial defense of the liver is limited. We investigated hepatic expression and regulation of antimicrobial peptides with focus on the human beta defensin-1 (hBD-1). Methods: Radial diffusion assay was used to analyze antimicrobial activity of liver tissue. Different defensins including hBD-1 and its activator thioredoxin-1 (TXN) were analyzed in healthy and cholestatic liver samples by qPCR and immunostaining. Regulation of hBD-1 expression was studied in vitro and in vivo using bile duct-ligated mice. Regulation of hBD-1 via bilirubin and bile acids (BAs) was studied using siRNA. Results: We found strong antimicrobial activity of liver tissue against Escherichia coli. As a potential mediator of this antimicrobial activity we detected high expression of hBD-1 and TXN in hepatocytes, whereas other defensins were minimally expressed. Using a specific antibody for the reduced, antimicrobially active form of hBD-1 we found hBD-1 in co-localization with TXN within hepatocytes. hBD-1 was upregulated in cholestasis in a graded fashion. In cholestatic mice hepatic AMP expression (Defb-1 and Hamp) was enhanced. Bilirubin and BAs were able to induce hBD-1 in hepatic cell cultures in vitro. Treatment with siRNA and/or agonists demonstrated that the farnesoid X receptor (FXR) mediates basal expression of hBD-1, whereas both constitutive androstane receptor (CAR) and FXR seem to be responsible for the induction of hBD-1 by bilirubin. Conclusion: hBD-1 is prominently expressed in hepatocytes. It is induced during cholestasis through bilirubin and BAs, mediated by CAR and especially FXR. Reduction by TXN activates hBD-1 to a potential key player in innate antimicrobial defense of the liver.