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Background and aimsNon-alcoholic fatty liver disease (NAFLD) is a global health burden. Risk factors for disease severity include older age, increased body mass index (BMI), diabetes, genetic variants, dietary factors and gut microbiota alterations. However, the interdependence of these factors and their individual impact on disease severity remain unknown.MethodsIn this cross-sectional study, we performed 16S gene sequencing using fecal samples, collected dietary intake, PNPLA3 gene variants and clinical and liver histology parameters in a well-described cohort of 180 NAFLD patients. Principal component analyses were used for dimensionality reduction of dietary and microbiota data. Simple and multiple stepwise ordinal regression analyses were performed.ResultsComplete data were available for 57 NAFLD patients. In the simple regression analysis, features associated with the metabolic syndrome had the highest importance regarding liver disease severity. In the multiple regression analysis, BMI was the most important factor associated with the fibrosis stage (OR per kg/m2 : 1.23, 95% CI 1.10-1.37, P&nbsp

Bacteria, archaeae, fungi and viruses of the intestinal microbiome play an important role as symbionts in the complex human ecosystem. Parasites, which account for about 40 % of the earth's biodiversity, depend on hosts to complete their life cycle. This article explains how they use them and which signalling pathways play a role in this, using toxoplasmosis and malaria as examples. The parasitic manipulation hypothesis is based on impressive observations in the wild and under laboratory conditions, especially in invertebrates. For the assumption of an adaptive manipulation, every step from the genotype, the translated messenger, and its source via the used signalling pathways to the altered host behaviour must be proven. The assumption of an adaptive manipulation of humans by T. gondii in the sense of a cause-effect relationship is not proven. Alternative explanations include the inflammatory and immunological processes on the host side, which change the neuronal signal transduction as concomitant symptoms of an infection. Even without confirmation of parasitic manipulation in humans, it could be worthwhile to further investigate the observed associations in order to develop new possibilities for diagnosis and therapy, e. g. for schizophrenia.

Sepsis represents a life-threatening condition that frequently accompanies acute hepatic dysfunction. As a result of systemic inflammation, immune dysregulation, and microcirculatory derangements, different types of liver dysfunction can occur, such as hypoxic hepatitis, sepsis-associated cholestasis, or liver failure. A very serious and late sequela is secondary sclerosing cholangitis of the critically ill patient. Clinical management of sepsis-related liver dysfunction includes the rapid identification and treatment of the suspected underlying infection, hemodynamic stabilization to improve hepatic perfusion, and the optimization of oxygen delivery to the liver. Despite maximum efforts in supportive treatment, the outcome of patients with sepsis or septic shock and concomitant severe hepatic dysfunction remains very poor.

Non-alcoholic fatty liver DISEASE (NAFLD) is the most common chronic liver disease in Western countries and affects approximately 25% of the adult population. Since NAFLD is frequently associated with further metabolic comorbidities such as obesity, type 2 diabetes mellitus, or dyslipidemia, it is generally considered as the hepatic manifestation of the metabolic syndrome. In addition to its potential to cause liver-related morbidity and mortality, NAFLD is also associated with subclinical and clinical cardiovascular disease (CVD). Growing evidence indicates that patients with NAFLD are at substantial risk for the development of hypertension, coronary heart disease, cardiomyopathy, and cardiac arrhythmias, which clinically result in increased cardiovascular morbidity and mortality. The natural history of NAFLD is variable and the vast majority of patients will not progress from simple steatosis to fibrosis and end stage liver disease. However, patients with progressive forms of NAFLD, including non-alcoholic steatohepatitis (NASH) and/or advanced fibrosis, as well as NAFLD patients with concomitant types 2 diabetes are at highest risk for CVD. This review describes the underlying pathophysiological mechanisms linking NAFLD and CVD, discusses the role of NAFLD as a metabolic dysfunction associated cardiovascular risk factor, and focuses on common cardiovascular manifestations in NAFLD patients.

Background: Cardiovascular disease and especially hypertension are a growing problem among people living with HIV (PLHIV) on antiretroviral therapy (ART) in sub-Saharan Africa. Objectives: As robust data on hypertension phenotypes associated with distinct cardiovascular risks among PLHIV are limited, we aimed to assess the frequency of white-coat (WCH), masked (MH) hypertension, and blood pressure dipping-patterns in a group of Malawian PLHIV. Methods: As part of the prospective Lighthouse-Tenofovir-Cohort-Study, we analyzed clinical, laboratory and 24-h-ambulatory blood pressure monitoring (ABPM) data of PLHIV from urban Lilongwe with treated or untreated hypertension or raised office blood pressure (OBP) during routine study-visits. Results: 118 PLHIV were included and data of 117 participants could be analyzed. Twenty–four-hour ABPM normotension was found in a total of 73 PLHIV including 14/37 on antihypertensive treatment (37.8%). Using strict definitions, i.e. normal OBP plus normal mean BP for all periods of ABPM, controlled hypertension was found in only 4/37 (10.8%) PLHIV on antihypertensive treatment while true normotension was observed in 10/24 untreated patients (41.7%) with previously diagnosed hypertension and 22/56 patients (39.3%) without a medical history of hypertension. WCH with normal BP during all periods of 24-h-ABPM was identified in 12/64 OBP-hypertensive PLHIV (18.8%), primarily in patients with grade 1 hypertension (11/41 patients; 26.8%). MH was found in 17/53 PLHIV with OBP-normotension (32.1%), predominantly in patients with high normal BP (11/20 patients; 55%). The estimated glomerular filtration rate tended to be lower in MH compared to strictly defined normotensive PLHIV (92.0±20.4 vs. 104.8±15.7 ml/min/m²). 64.1 percent of PLHIV (59.5% with 24-h hypertension and 66.7% with 24-h normotension) had abnormal systolic dipping. Conclusion: The high prevalence of WCH and MH with signs of early renal end-organ damage and an abnormal dipping in approximately 2/3 of PLHIV warrants further investigation as these factors may contribute to the increased cardiovascular risk in PLHIV in resource-limited settings like Malawi. Clinical Trial Registration: https://clinicaltrials.gov (NCT02381275), registered March 6th, 2015.

ZUSAMMENFASSUNGKardiovaskuläre Erkrankungen wie die arterielle Hypertonie gewinnen in Subsahara-Afrika neben infektiösen Erkrankungen zunehmend an Bedeutung. Die ambulante 24-h-Blutdruck-Langzeitmessung (24-h-ABDM) ist das Verfahren der Wahl zur Diagnosesicherung einer Hypertonie. Als Teil der LighTen Cohort Study hat diese Untersuchung das Ziel, die Machbarkeit einer 24-h-ABDM und ihre Bedeutung für Diagnose und Management des Hochdrucks bei HIV+-Patienten unter antiretroviraler Therapie zu bestimmen. Analysiert wurden die Praxis-Blutdruckwerte und 24-h-ABDM-Daten 34 erwachsener HIV+-Patienten sowie die Daten von 20 HIV--Kontrollpersonen. Bei einem Viertel der antihypertensiv behandelten Patienten und Kontrollen war der Blutdruck kontrolliert. Die 24-h-ABDM-Untersuchung erwies sich unter den Bedingungen eines Entwicklungslandes als machbar und identifizierte Patienten mit prognostisch ungünstigem nächtlichem Blutdruckverhalten sowie Patienten mit Weißkittelhypertonie und wahrscheinlich guter Prognose.

Der kardiogene Schock ist ein lebensbedrohlicher Zustand, der haufig mit einer akuten Organdysfunktion der Leber einhergeht. Infolge einer verminderten kardialen Pumpleistung mit konsekutiver Hypoperfusion und inadaquater Sauerstoffversorgung der Leber konnen sich verschiedene Formen einer akuten Leberfunktionsstorung entwickeln, so etwa eine hypoxische Hepatitis oder akute Leberinsuffizienz. Eine gefurchtete lebensbedrohliche Komplikation ist die sekundar sklerosierende Cholangitis. Wesentliche Therapiemasnahmen beinhalten die Stabilisierung der hamodynamischen Situation mit Optimierung der kardialen Auswurfleistung zur Verbesserung der systemischen Perfusion sowie die Verbesserung der hepatischen Sauerstoffversorgung. Insgesamt ist das kombinierte Auftreten eines kardiogenen Schocks und einer schweren hepatischen Dysfunktion mit einer schlechten Prognose assoziiert.

Background Cronkhite-Canada syndrome is a rare disease of unknown etiology and the optimal treatment for this syndrome is unknown. Case presentation We present the case of a man who at the age of 66.0 years was diagnosed with Cronkhite-Canada syndrome (CCS). In addition to watery diarrhea, alopecia, and a complete loss of toenails and fingernails, the patient had been suffering from dysgeusia and rapid weight loss of more than 10.0 kg within a few months. The patient had recently incurred a distal radius fracture. During the initial endoscopy an extensive polyposis of the stomach and jejunum was found. The diagnosis of CCS was made and after initiation of a steroid therapy his diarrhea improved immediately. A discontinuation of the steroid therapy was not possible and mesalazine (1000 mg t.i.d.) was added to prednisolone (10.0 mg/d). This therapy led to a remission within 6.0 months with weight gain and normalization of serum albumin levels. The prednisolone dose was reduced to 7.5 mg/d. During the following year, the steroids could be further reduced and nails had regrown again. Within three years, all polyps had disappeared and the steroid therapy was finished while the dosage of mesalazine was reduced in a stepwise fashion. Four years later, the mesalazine was stopped and more than 14.0 years after the initial diagnosis the patient is still in complete remission without any treatment. Conclusion The optimal treatment for CCS is unknown. In our case, the initial combination therapy of corticosteroids plus mesalazine followed by a mesalazine monotherapy has led to a remarkable long-lasting remission with complete resolution of all intestinal polyps.

Background & Aims Alterations in the gut microbiome have been associated with the severity of nonalcoholic fatty liver disease (NAFLD). Previous studies focused exclusively on the bacteria in the microbiome; we investigated changes in the viral microbiome (virome) in patients with NAFLD. Methods In a prospective, cross-sectional, observational study, we extracted RNA and DNA virus-like particles from fecal samples from 73 patients with NAFLD: 29 patients had an NAFLD Activity Score (NAS) of 0–4, 44 patients had an NAS of 5–8 or liver cirrhosis (LCI), 37 patients had F0–F1 fibrosis, and 36 patients had F2–F4 fibrosis. As controls, 9 individuals without liver disease and 13 patients with mild primary biliary cholangitis were included in the analysis. We performed shotgun metagenomic sequencing of virus-like particles. Results Patients with NAFLD and NAS 5–8/LCI had a significant decrease in intestinal viral diversity compared with patients with NAFLD and NAS 0–4 or control individuals. The presence of more advanced NAFLD was associated with a significant reduction in the proportion of bacteriophages compared with other intestinal viruses. Using multivariate logistic regression analysis with leave-1-out cross validation, we developed a model, including a viral diversity index and simple clinical variables, that identified patients with NAS 5–8/LCI with an area under the curve of 0.95 (95% confidence interval, 0.91–0.99) and F2–F4 fibrosis with an area under the curve of 0.88 (95% confidence interval, 0.80–0.95). Addition of data on viral diversity significantly improved multivariate models, including those based on only clinical parameters or bacterial diversity. Conclusions In a study of fecal viromes from patients with NAFLD and control individuals, we associated histologic markers of NAFLD severity with significant decreases in viral diversity and proportion of bacteriophages. We developed a model based on fecal viral diversity and clinical data that identifies patients with severe NAFLD and fibrosis more accurately than models based only on clinical or bacterial data.

Background and aims: Adenoma detection rate (ADR) is a key quality indicator for colonoscopy; however, it is cumbersome to obtain. We investigated if detection rates (DRs) for adenomas, serrated polyps (SPs) and clinically relevant SP (crSPDR) can be accurately estimated by individualized DR ratios (DRRs) in a multicenter primary colonoscopy screening cohort of average-risk individuals. Methods: DRRs were calculated by dividing DRs for a certain polyp entity by polyp detection rate (PDR) for each endoscopist individually on the basis of his/her first 50 (DRR50) and 100 (DRR100) consecutive colonoscopies. DRs were estimated for each endoscopist by multiplying his/her DRR for a certain polyp entity with his/her PDR of subsequent colonoscopies in groups of 50 (DRR50) and 100 (DRR100) consecutive colonoscopies. Estimated and actual DRs were compared. Results: Estimated DRs showed a strong correlation with actual DRs for adenomas (r = 0.86 and 0.87; each p < .001), SPs (r = 0.85 and 0.91; each p < .001) and crSPs (r = 0.82 and 0.86; each p < .001) using DRRs derived from first 50 and 100 consecutive colonoscopies. Corresponding root mean square error (RMSE) between individual estimated and actual DRs using DRR50 and DRR100 was 5.3(±4.6)% and 4.5(±4.8)% for adenomas, 5.2(±4.1)% and 3.9(±2.8)% for SP, 3.1(±3.1)% and 2.8(±2.5)% for crSP, respectively. RMSE was not significantly different between DRR50 and DRR100 for ADR (p = .445), SPDR (p = .178) and crSP (p = .544). Conclusions: DR for all relevant polyp entities can be accurately estimated by using individual DRRs. This approach may enable endoscopists to easily track their performance measures in daily routine.

Background Pre-treatment drug resistance (PDR) among antiretroviral drug-naïve people living with HIV (PLHIV) represents an important indicator for the risk of treatment failure and the spread of drug resistant HIV variants. We assessed the prevalence of PDR and treatment outcomes among adults living with HIV-1 in Lilongwe, Malawi. Methods We selected 200 participants at random from the Lighthouse Tenofovir Cohort Study (LighTen). Serum samples were drawn prior to treatment initiation in 2014 and 2015, frozen, and later analyzed for the presence of HIV-1 drug resistance mutations. Amplicons were sequenced and interpreted by Stanford HIVdb interpretation algorithm 8.4. We assessed treatment outcomes by evaluating clinical outcome and viral suppression at the end of the follow-up period in October 2019. Results PDR testing was successful in 197 of 200 samples. The overall NNRTI- PDR prevalence was 13.7% (27/197). The prevalence of intermediate or high level NNRTI- PDR was 11.2% (22/197). The most common mutation was K103N (5.6%, 11/197), followed by Y181C (3.6%, 7/197). In one case, we detected an NRTI resistance mutation (M184V), in combination with multiple NNRTI resistance mutations. All HIV-1 isolates analyzed were of subtype C. Of the 27 patients with NNRTI- PDR, 9 were still alive, on ART, and virally suppressed at the end of follow-up. Conclusion The prevalence of NNRTI- PDR was above the critical level of 10% suggested by the Global Action Plan on HIV Drug Resistance. The distribution of drug resistance mutations was similar to that seen in previous studies from the region, and further supports the introduction of integrase inhibitors in first-line treatment in Malawi. Furthermore, our findings underline the need for continued PDR surveillance and pharmacovigilance in Sub-Saharan Africa.

BACKGROUND AND AIM The aim of the study was to analyze the diagnostic performance and clinical utility of simple noninvasive tests for the detection of advanced fibrosis in patients with chronic hepatitis B (CHB) infection seen at a tertiary referral center in Germany. PATIENTS AND METHODS We retrospectively analyzed 239 adult CHB patients with available liver biopsies. Patient demographics, hepatitis B markers, antiviral treatment, laboratory parameters, results from liver imaging, and histology were recorded. The sensitivity, specificity, and positive and negative predictive values were determined along with the area under receiver operating characteristic curves (AUROC) using published formulas and cut-off values for fibrosis index based on the four factors, aspartate aminotransferase-alanine aminotransferase ratio index (AAR), aspartate aminotransferase-to-platelet ratio index (APRI), and age-platelet index. RESULTS The median documented duration of CHB infection was 31 months (range: 6-340 months); 86% of the patients were Caucasian and 71% were men. The AUROCs for the detection of advanced fibrosis were 0.75 [95% confidence interval (CI): 0.67-0.82], 0.72 (95% CI: 0.64-0.80), 0.48 (95% CI: 0.39-0.56), and 0.73 (95% CI: 0.66-0.81) for fibrosis index the four factors, APRI, AAR, and age-platelet index, respectively. Patients with advanced fibrosis on biopsy were misclassified as having mild fibrosis in 35% (APRI) to 82% (AAR) of cases. CONCLUSION Because of their moderate test performance (AUROCs: 0.48-0.75) and their high misclassification rate, we could not confirm a reliable clinical utility for the analyzed noninvasive fibrosis scoring systems for the prediction of advanced fibrosis in mostly Caucasian CHB patients.

International audience; Chronic infection with hepatitis C virus (HCV) is one of the main causes of hepatocellular carcinoma. However, the molecular mechanisms linking the infection to cancer development remain poorly understood. Here we used HCV-infected cells and liver biopsies to study how HCV modulates the glutaminolysis pathway, which is known to play an important role in cellular energetics, stress defense and neoplastic transformation. Transcript levels of glutaminolytic factors were quantified in Huh7.5 cells or primary human hepatocytes infected with the JFH1 HCV strain as well as in biopsies of chronic HCV patients. Nutrient deprivation, biochemical analysis and metabolite quantification were performed with JFH1 infected Huh7.5 cells. Furthermore, shRNA vectors and small molecule inhibitors were used to investigate the dependence of HCV replication on metabolic changes. We show that HCV modulates the transcript levels of key enzymes of the glutamine metabolism in vitro and in liver biopsies of chronic HCV patients. Consistently, HCV infection increases glutamine utilization and dependence. We finally show that inhibiting glutamine metabolism attenuates HCV infection and the oxidative stress associated with HCV infection. Conclusions Our data suggest that HCV establishes glutamine dependence, which is required for viral replication. Importantly, glutamine addiction is also a hallmark of tumor cells. While HCV induces glutaminolysis to create an environment favorable for viral replication, it predisposes the cell to transformation. Glutaminolytic enzymes may be interesting therapeutic targets for prevention of hepatocarcinogenesis in chronic hepatitis C. This article is protected by copyright. All rights reserved

Background Current guidelines for clinical practice recommend the infusion of human albumin after large volume paracentesis. After inspecting the current evidence behind this recommendation, we decided to conduct a systematic review and meta-analysis in order to address the effect of albumin on mortality and morbidity in the context of large volume paracentesis. Methods We performed a comprehensive search of large databases and abstract books of conference proceedings up to March 15th 2016 for randomized controlled trials, testing the infusion of human albumin against alternatives (vs no treatment, vs plasma expanders; vs vasoconstrictors) in HCC-free patients suffering from cirrhosis. We analyzed these trials with regard to mortality, changes in plasma renin activity (PRA), hyponatremia, renal impairment, recurrence of ascites with consequential re-admission into hospital and additional complications. We employed trial sequential analysis in order to calculate the number of patients required in controlled trials to be able to determine a statistically significant advantage of the administration of one agent over another with regard to mortality. Results We were able to include 21 trials totaling 1277 patients. While the administration of albumin prevents a rise in PRA as well as hyponatremia, no improvement in strong clinical endpoints such as mortality could be demonstrated. Trial sequential analysis showed that at least 1550 additional patients need to be recruited into RCTs and analyzed with regard to this question in order to detect or disprove a 25% mortality effect. Conclusions There is insufficient evidence that the infusion of albumin after LVP significantly lowers mortality in HCC-free patients with advanced liver disease.

Objective: International guidelines recommend hepatocellular carcinoma (HCC) surveillance with ultrasound in high-risk patients with chronic liver diseases. However, there is low-strength evidence ...

Background and aim Several studies observed alterations in the gut microbiota in patients with non-alcoholic fatty liver disease (NAFLD). However, analyzed patient populations and methods strongly differ among these studies. The aim of this study was to prove the reproducibility of published results and to provide a detailed overview of all findings in our NAFLD cohort using next generation sequencing methods. Methods The individual taxonomic microbiota composition of fecal samples from 90 NAFLD patients and 21 healthy controls was analyzed using 16S rRNA gene sequencing. Study participants were grouped according to their disease stage and compared regarding their gut microbiota composition. Studies were identified from PubMed listed publications, and the results were compared with the findings in our cohort. Results Results from 13 identified studies were compared with our data. A decreased abundance of the Bacteroidetes and Ruminococcaceae as well as an increased abundance of Lactobacillaceae and Veillonellaceae and Dorea were the most frequently reported changes among NAFLD patients in 4/13, 5/13, 4/13, 2/13, and 3/13 studies, respectively. Even though these alterations in the gut microbiota composition were also observed in our patient cohort, the majority of published differences could not be reproduced, neither in our own nor in other NAFLD cohort studies. Conclusion Despite repeatedly reproduced abundance patterns of specific bacteria, the heterogeneous study results did not reveal a consistent disease specific gut microbiota signature. Further prospective studies with homogenous patient cohorts and standardized methods are necessary to phenotype NAFLD by the gut microbiota.

Overconsumption of carbohydrates and lipids are well known to cause nonalcoholic fatty liver disease (NAFLD), while the role of nutritional protein intake is less clear. In Western diet, meat and other animal products are the main protein source, with varying concentrations of specific amino acids. Whether the amount or composition of protein intake is associated with a higher risk for disease severity has not yet been examined. In this study, we investigated associations of dietary components with histological disease activity by analyzing detailed 14-day food records in a cohort of 61 patients with biopsy-proven NAFLD. Furthermore, we used 16S ribosomal RNA gene sequencing to detect associations with different abundances of the gut microbiota with dietary patterns. Patients with definite nonalcoholic steatohepatitis (NAFLD activity score of 5-8 on liver biopsy) had a significantly higher daily relative intake of protein compared with patients with a NAFLD activity score of 0-4 (18.0% vs. 15.8% of daily protein-based calories, P = 0.018). After adjustment for several potentially confounding factors, a higher protein intake (≥17.3% of daily protein-based calories) remained associated with definite nonalcoholic steatohepatitis, with an odds ratio of 5.09 (95% confidence interval 1.22-21.25, P = 0.026). This association was driven primarily by serine, glycine, arginine, proline, phenylalanine, and methionine. A higher protein intake correlated with a lower Bacteroides abundance and an altered abundance of several other bacterial taxa. Conclusion: A high protein intake was independently associated with more active and severe histological disease activity in patients with NAFLD. Further studies are needed to investigate the potential harmful role of dietary amino acids on NAFLD, with special attention to meat as their major source.

Background: In a previous publication, a FIB-4 cutoff value of ≥ 1.25, which had been determined in an Asian population, did not allow reliable prediction of the development of hepatocellular carcinoma (HCC) in a patient collective with chronic hepatitis B (CHB) of predominantly non-Asian descent. Objectives: Here, we aimed to validate the modified FIB-4 cutoff values as a means of stratifying the HCC risk in a non-Asian cohort seen at an outpatient university hospital liver unit in Germany. Methods: We retrospectively analyzed 350 adult patients with CHB infection. We recorded demographics, laboratory parameters, results from liver imaging, serological hepatitis B markers, antiviral treatment, and histology. We separated patients into two groups based on individual FIB-4 levels. We, then, analyzed the patients’ hazard ratios for HCC and adjusted it for sex, age, antiviral medication, duration of CHB infection, body mass index, alcohol consumption, and type 2 diabetes. An additional sub-analysis was performed by including only non-cirrhotic patients to determine the validity of the proposed cutoffs in that cohort. Results: The median duration of follow-up was 8.9 years with a range of 1 - 21.3 years. Our patients were 65% males. In comparison with patients that had a low FIB-4 (< 0.3635), those with elevated FIB-4 (≥ 0.3635) had an HCC incidence hazard ratio of 11.67 (95% confidence interval (CI): 2.73 - 49.96; P = 0.001) and an adjusted hazard ratio of 7.90 (95% CI: 1.58 - 39.39; P = 0.012). Elevated FIB-4 non-cirrhotic patients had a hazard ratio (HR) of 15.88 (95% CI: 2.04 - 123.20) for HCC incidence (P < 0.0001) and an adjusted HR of 11.99 (95% CI: 1.36 - 105.72) (P = 0.001). Conclusions: A FIB-4 value of < 0.3635 appears to be a clinical indicator for a low likelihood of HCC incidence in non-Asian patients with CHB with or without cirrhosis. Further studies in patients of diverse descent are necessary to prove its utility as a clinical tool in this setting.

Maternal obesity is associated with an increased risk of hepatic metabolic dysfunction for both mother and offspring and targeted interventions to address this growing metabolic disease burden are urgently needed. This study investigates whether maternal exercise (ME) could reverse the detrimental effects of hepatic metabolic dysfunction in obese dams and their offspring while focusing on the AMP-activated protein kinase (AMPK), representing a key regulator of hepatic metabolism. In a mouse model of maternal western-style-diet (WSD)-induced obesity, we established an exercise intervention of voluntary wheel-running before and during pregnancy and analyzed its effects on hepatic energy metabolism during developmental organ programming. ME prevented WSD-induced hepatic steatosis in obese dams by alterations of key hepatic metabolic processes, including activation of hepatic ß-oxidation and inhibition of lipogenesis following increased AMPK and peroxisome-proliferator-activated-receptor-γ-coactivator-1α (PGC-1α)-signaling. Offspring of exercised dams exhibited a comparable hepatic metabolic signature to their mothers with increased AMPK-PGC1α-activity and beneficial changes in hepatic lipid metabolism and were protected from WSD-induced adipose tissue accumulation and hepatic steatosis in later life. In conclusion, this study demonstrates that ME provides a promising strategy to improve the metabolic health of both obese mothers and their offspring and highlights AMPK as a potential metabolic target for therapeutic interventions.

Die Hypertonie ist eine Zivilisationskrankheit, das wissen die meisten. Aber wie ist sie genau definiert, wie haufig ist sie in Deutschland und wie ist der gegenwartige Stand der Therapie? Die folgenden Seiten geben Antworten auf diese Fragen.

Die bisher veröffentlichte Studienlage zur Assoziation von Kolondivertikeln und kolorektalen Polypen einschließlich des kolorektalen Karzinoms (KRK) ist konträr. Ziel der Studie war es, die Assoziation für sämtliche relevanten histologischen Polypensubtypen, d. h. hyperplastische Polypen (HP), sessil und traditionell serratierte Adenome (SSA und TSA), klinisch relevante serratierte Polypen (krSP), tubuläre Adenome und fortgeschrittene Adenome in einer ausschließlichen Vorsorgekoloskopie-Kohorte zu untersuchen. Wir führten eine retrospektive Analyse von Personen ≥ 50 Jahre und einem durchschnittlichen Risiko für ein KRK, die eine Vorsorgekoloskopie zwischen dem 01.01.2012 und dem 14.12.2016 in einer Universitätsklinik und 6 gastroenterologischen Schwerpunktpraxen erhalten haben, durch. Ausschlusskriterien waren Erkrankungen mit einem erhöhten KRK-Risiko (z. B. chronisch-entzündliche Darmerkrankungen, KRK in der Vorgeschichte, hereditäre Karzinomsyndrome), eine vorherige Koloskopie und eine unvollständige Untersuchung. 4196 Koloskopien wurden eingeschlossen (mittleres Alter 63,4 Jahre, Standardabweichung ± 7,6 Jahre, 48,6 %). Bei Vorliegen von Divertikeln zeigten sich nach Adjustierung für Alter und Geschlecht erhöhte Odds-Ratios (OR) für den Nachweis von HP im gesamten (OR 1,340, 95 %-Konfidenzintervall 1,133 - 1,584, p = 0,001) und im distalen Kolon (OR 1,459, 95 %-KI 1,208 - 1,763, p 0,001) sowie von tubulären Adenomen im distalen Kolon (OR 1,355, 95 %-KI 1,144 - 1,604, p 0,001). Die mittlere Polypenanzahl pro Untersuchung mit dem Nachweis von mindestens einem Polypensubtypen unterschied sich nicht zwischen beiden Gruppen. Die Untersucher sollten beim Vorliegen einer Divertikulose wachsam für den Nachweis von vor allem distal gelegenen Adenomen sein. Studies investigating the association between colonic diverticula and colorectal polyps and colorectal cancer (CRC) have reported conflicting results. We aimed to evaluate this association for all relevant different histological polyp subtypes (i. e., hyperplastic polyps [HPs], sessile and traditionally serrated adenomas, clinically relevant serrated polyps, nonadvanced and advanced adenomas) in an exclusive colonoscopy screening cohort. We conducted a retrospective analysis of individuals ≥ 50 years of age with an average risk for CRC who underwent a screening colonoscopy between January 1, 2012, and December 14, 2016, at a tertiary academic hospital and 6 community-based private practices. Exclusion criteria were conditions with increased risk for CRC (e. g., inflammatory bowel disease, history of CRC, hereditary cancer syndromes), previous colonoscopy at the same institution, and incomplete procedures. A total of 4196 colonoscopies were included (mean age: 63.4, standard deviation: ± 7.6 years, 48.6 % men). In the presence of colonic diverticula, significantly increased odds ratios (OR) were found for the detection of HPs overall (OR: 1.340, 95 % confidence interval [CI]: 1.133 – 1.584, p = 0.001) and in the distal colon (OR: 1.459, 95 % CI: 1.208 – 1.763, p 0.001), as well as for nonadvanced adenomas (OR: 1.355, 95 % CI: 1.144 – 1.604, p 0.001) in the distal colon after adjusting for age and gender. The mean numbers of different histological polyp subtypes detected per procedure with at least one of the histological polyp subtype did not differ between both groups. Endoscopists should be vigilant for the detection of adenomatous polyps in the distal colon when diverticula are present during colonoscopy.

Background Serrated polyps have been recognized as precursors of colorectal cancer (CRC) via the serrated pathway. Endoscopic detection and histopathological evaluation of serrated polyps are challenging. The aims of this study were to determine detection rates of the recently proposed entity of clinically relevant serrated polyps (crSPs) and to identify factors that influence their detection in a primary colonoscopy screening cohort. Methods We retrospectively analyzed average-risk screening colonoscopies performed at a tertiary academic hospital and six community-based private practices in Germany between 01/01/2012 and 14/12/2016. Exclusion criteria were age 5 mm located proximally to the splenic flexure. Conventional adenomas were defined as adenomas excluding serrated polyps. Results A total of 4161 colonoscopies from average-risk individuals were included (median age 62 years [interquartile range 56 – 69]; 48.6 % male). CrSPs were detected in 6.9 %, with a mean detection rate of 4.7 % (95 % confidence interval 2.3 % – 7.2 %). Detection rates ranged from 0 % to 16.2 %. In multivariate analysis, simultaneous detection of conventional adenomas and an endoscopist adenoma detection rate of ≥ 25 % were significantly associated with increased detection of crSPs, with odds ratios of 1.43 (95 %CI 1.11 – 1.85; P = 0.01) and 7.35 (95 %CI 4.43 – 12.19; P Conclusion Detection rates for crSPs differed between participating endoscopists. However, individual skills to detect polypoid lesions have a relevant bearing on the detection rate of crSPs.

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease worldwide with a reported prevalence ranging 6-33%, depending on the studied populations. It encompasses a spectrum of liver manifestations ranging from simple steatosis (also known as nonalcoholic fatty liver, NAFL) to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, which may ultimately progress to hepatocellular carcinoma. NAFLD is strongly associated with the components of metabolic syndrome, mainly obesity and type 2 diabetes mellitus. NAFLD patients are at increased risk of liver-related as well as cardiovascular mortality. Current paradigm suggests a benign course for NAFL whereas NASH is considered to be the progressive phenotype. Although previously under-recognized accumulating evidence suggests that NAFL may also progress, suggesting a higher number of patients at risk than previously appreciated. Liver biopsy remains the gold standard for definitive diagnosis, but the majority of patients can be diagnosed accurately by noninvasive methods. Approved therapies for NAFLD are still lacking and lifestyle modifications aiming at weight loss remain the mainstay of NAFLD treatment. Intensive research could identify insulin resistance, lipotoxicity and dysbiosis of the gut microbiota as major pathophysiological mechanisms, leading to the development of promising targeted therapies which are currently investigated in clinical trials. In this review we summarized the current knowledge of NAFLD epidemiology, natural history, diagnosis, pathogenesis and treatment and considered future directions.

A substantial interobserver variation in the differential diagnosis of hyperplastic polyps (HPs) and sessile or traditional serrated adenomas (SSAs/TSAs) has been described.The aim of this study is to determine the magnitude of reclassification of HPs and associated factors after pathological reassessment of specimens from screening and surveillance colonoscopies, and to estimate its consequences for follow-up recommendations.Among 1694 screening and surveillance colonoscopies, a total of 536 polyps were initially diagnosed as HPs and remained unchanged in 88.5% (n = 474), whereas 7.6 (n = 41) and 1.1% (n = 6) were reclassified as SSA and TSA, respectively. Compared to definite HPs, SSAs were found more frequently in men than in women (82.9 vs. 61.2%, p 0.05), and in individuals ≥65.0 years (51.2 vs. 31.6%, p = 0.05). Also, more SSAs were5 mm in size (36.6 vs. 6.3%, p 0.05) and were localized in the proximal colon (31.7 vs. 11.8%, p 0.05). In a mixed model analysis, age ≥65.0 years (OR 4.13, 95% CI 1.22-14.2), snare polypectomy (OR 23.6, 95% CI 4.86-115), and coincident advanced adenomas (OR 7.56, 95% CI 1.31-43.5) were significantly (p 0.05) associated with reclassification to SSAs. Only 0.53% of patients had received false recommendations for follow-up visits based on the incorrect HP diagnosis. A c.1799TA, p.V600E BRAF mutation was detected in 21.9 % (n = 9) of reclassified SSAs.Considering these factors may be helpful in serrated lesions that are difficult to allocate. Incorrect recommendations regarding control colonoscopy intervals due to misdiagnosed HPs can explain only a small fraction of interval colorectal cancers.

Helicobacter pylori (Hp) infection has been hypothesised to play a major role in the pathogenesis of chronic spontaneous urticaria (CSU). Despite only weak evidence from Hp eradication studies, screening for Hp infection is still recommended in several CSU guidelines. The aim of this study was to investigate the effect of Hp eradication in combination with standard CSU treatment in Hp-positive compared with Hp-negative patients, applying the latest guidelines for both diseases. 138 consecutive patients with CSU were enrolled in this retrospective cohort study. All patients underwent gastroscopy and Hp status was determined by urease testing and histologic examination. Seventy-five patients were diagnosed as Hp negative and 47 patients fulfilled criteria for definite Hp infection, 45 of whom received eradication therapy. Sixteen patients who received eradication therapy without an appropriate indication served as the medication control. All patients received symptomatic treatment with antihistamines and/or glucocorticoids regardless of Hp status. Partial response (PR) was defined as subjective amelioration of CSU symptoms; patients returning for further CSU treatment within 6 months were considered non-responders/relapsers (NRs). The prevalence of Hp infection was comparable with Hp seroprevalence data reported for healthy western populations. Standard treatment of CSU led to relief of symptoms independent of Hp status. Hp eradication by standard triple therapy had no additional effect on PR (p = 0.32) or NR (p = 0.50). Hp eradication has no discernible effect on CSU beyond that of standard CSU therapy. Therefore, Hp eradication should only be initiated in accordance with currently accepted indications of Hp treatment guidelines.

Screening colonoscopy is less effective in reducing the incidence of proximal compared to distal colorectal cancer, presumably because of missed adenomas and advanced lesions during endoscopy. Thus, effectiveness and success of colorectal cancer (CRC) screening programs depend decisively on the quality of the endoscopic procedures. A retrospective analysis of 1603 average risk screening colonoscopies to calculate and to identify determinants of separate detection rates for proximally and distally located polyps, adenomas, and advanced adenomas was performed. 56.1 % of 1603 individuals included were men, and the mean age was 60.2 ± 10.2 years. Distal detection rates were markedly higher compared to proximal detection rates for polyps (40.9 vs. 23.8 %), adenomas (21.3 vs. 16.2 %), and advanced adenomas (4.0 vs. 2.0 %). A gradual increase in detection rates with increasing age was found for proximal and distal localization. Gender difference was also seen for polyps and adenomas, but not for advanced adenomas. In multivariate analysis, age

Neuroendocrine carcinomas represent a heterogeneous tumor entity, which can occur in almost all organ systems of the human body. The worldwide incidence, approximately 0.5– 5/100.000, is low, with almost 70 % occurring in the digestive sys t em , ano the r 20 % be ing d i agnosed in the bronchopulmonary tract. Data from autopsy studies suggest that neuroendocrine tumors are an under-recognized malignancy [3]. Only 0.2 % of all neuroendocrine tumors (NETs) are located in the gallbladder. The most important prognostic factor is the level of proliferation, which determines the tumor grading. Overall, poorly differentiated NETs are aggressive tumors bearing a poor prognosis.

Background Epidemiological studies have led to equivocal results concerning the role of arterial blood pressure as a risk factor for the development of glaucomatous damage and progressive visual field loss in glaucoma has been attributed to low nighttime blood pressure, especially when oral antihypertensives have been combined with beta-blocking eyedrops. In order to answer the question whether nocturnal blood pressure or blood pressure dip during ambulatory blood pressure monitoring are associated with progressive visual field loss we performed a systematic review and meta-analysis of studies in patients with primary open-angle glaucoma and normal tension glaucoma. Methods After searching MEDLINE, the Cochrane Library, and EMBASE, only 5 studies could be found reporting information on the method of ambulatory blood pressure measurements, separate data for daytime and nighttime blood pressure, definition of nocturnal blood pressure dip, and assessment of visual fields over a period of at least 2 years. Results There was no difference in mean systolic or diastolic diurnal and nocturnal blood pressure between patients with or without progressive visual field loss. The odds ratio for deteriorating visual fields over 2 years with nocturnal dips >10% in systolic or diastolic blood pressure was 3.32 (1.84-6.00) and 2.09 (1.20-3.64), respectively. Data allowing a separate analysis of over-dipping were not available. Conclusions Nocturnal blood pressure fall is a risk factor for progressive visual field loss in glaucoma. However, prospective studies are needed to define a tolerable degree of dipping. Antihypertensive therapy in glaucomatous patients should be controlled with ambulatory blood pressure monitoring.

We have read the article by Ijspeert et al with great interest as it comprises the largest series of colonoscopies concerning the serrated polyposis syndrome (SPS) published so far.1 SPS is characterised by multiple serrated polyps (SP) throughout the colon and it is associated with an increased risk of colorectal cancer (CRC).2 A 5-year cumulative incidence of CRC during surveillance after clearing of all relevant polyps of 1.5% has been reported.2 Recently published guidelines recommend resection of all clinically relevant lesions and starting annual colonoscopy surveillance thereafter.3 Therefore, early recognition and treatment of SPS is important to achieve low long-term risk of CRC.4 We retrospectively analysed 4161 primary screening colonoscopies of average-risk individuals aged ≥50 years performed by 15 different experienced gastroenterologists (≥300 colonoscopies of all indications per year during the …

Objective:Increasing survival rates in people living with HIV (PLHIV) on antiretroviral therapy (ART) in sub-Saharan Africa are accompanied by a rise in non-communicable diseases. Particularly arterial hypertension represents a growing problem. As part of the ongoing prospective LighTen Cohort Study

Aberrant activation of plasmacytoid dendritic cells (pDCs) with excessive production of interferon alpha (IFNα) represents one of the hallmarks of immune activation during chronic phase of human immunodeficiency virus (HIV) infection. A number of studies have shown that disruption of mucosal integrity in the gut is a cause of persistent immune activation. However, little is known about the role that pDCs play in this process, and our current understanding comes from the simian immunodeficiency virus macaque model. Thus, in the present study we sought to investigate the frequency and function of pDCs in peripheral blood and gut samples from HIV-infected individuals before and 6 months after initiation of antiretroviral therapy (ART). We show that circulating pDCs were depleted in ART-naive HIV+ patients, and upregulated the gut-homing receptor CD103 compared with uninfected controls. By converse, pDCs accumulated in the terminal ileum of ART-naive HIV individuals compared with controls. Baseline levels of IFNα production and markers of immune activation in gut samples of ART-naive HIV subjects were elevated. All these parameters declined after 6 months of ART. Our results suggest that in chronic HIV infection, pDCs migrate from peripheral blood to the gut-associated lymphatic tissue, where they may contribute to immune activation.

To the Editor: Throughout the world, ≈115 million persons have hepatitis C virus (HCV) antibodies, ≈37 million are infected with HIV type 1, and an estimated 2.3 million persons are infected with both viruses (1). The estimated prevalence of HIV infection among adults in Malawi is 9.1% (2). Data concerning HCV seroprevalence in Malawi are conflicting and range from 0.0% to 18.0%, depending on the studied population and the chosen methods for HCV infection diagnosis (3–6). In a recent study, researchers used stored blood samples (without HCV confirmatory assays) from studies in rural and urban Malawian populations (1989–2008); an HCV seroprevalence of 6.8% was found in HIV-positive patients (7). In contrast, in a cohort of HIV-negative mothers (2006–2010), only 0.5% were found to be HCV positive with confirmatory HCV testing by immunoblot (8). These studies were not included in a 2015 metaanalysis that estimated the seroprevalence of HCV infection and HIV/HCV co-infection in Malawi to be 7.7% and 2.0%, respectively (9). Liver disease progresses more rapidly in HIV/HCV co-infected patients than in HCV monoinfected patients (10), and the highly effective second-generation direct-acting antiviral therapies are less toxic than interferon-based treatment regimens. It is crucial to gather accurate epidemiologic information on the burden of HIV/HCV co-infection to support the design and implementation of HCV treatment initiatives in resource-limited settings such as sub-Saharan Africa.

Background Benefits of exercise to prevent non-communicable diseases are well-documented. Limited data exists to promote physical activity in healthy but sedentary and/or overweight people. Brief interventions within routine German health checks may be an effective way to reach these patients. Methods/design The quasi-experimental, multi-center prospective feasibility study is designed for general practices in Cologne (intervention group) and Düsseldorf (control group), up to 20 per region. Eight to 10 inactive and/or overweight patients per practice will be recruited for a total of 300. General practitioners and at least one of their nurses for the intervention group will be trained in motivational interviewing and familiarized with low-threshold recommendations for exercise (activities of daily life (ADL), target of 10,000 steps/day) and additional tools (pedometers, activity diaries). Participants in the control group will only receive general advice (150 min of exercise/week). The primary aims are to evaluate the feasibility of this intervention and to determine whether it is possible to reach a mean increase of 1000 steps/day in the target group within 6 months. Secondary objectives focus on the number of patients who reach a target of 10,000 steps/day and their improvements in quality of life and decrease in body mass index, waist circumference, and blood pressure. Discussion The study will assess whether it is feasible to run brief interventions within the GP setting can promote an active lifestyle in overweight and/or inactive patients. Electronic supplementary material The online version of this article (doi:10.1186/s40814-016-0092-9) contains supplementary material, which is available to authorized users.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease leading to cirrhosis and cholangiocellular carcinoma. Inhibitors of the renin-angiotensin system or the sympathetic nervous system delay liver fibrogenesis in animal models.We investigated the antifibrotic potential of telmisartan, an angiotensin II type 1 receptor antagonist, and the β-adrenoceptor blocker propranolol in the PSC-like Abcb4 knockout mouse model.Sixty-five Abcb4 (-/-) mice were treated with telmisartan for 3 or 5 months (T) and with telmisartan plus propranolol for 3, 5, or 8 months (TP), or for 2 or 5 months starting with a delay of 3 months (TP delayed). Liver hydroxyproline content, inflammation, fibrosis, and bile duct proliferation were assessed; fibrosis-related molecules were analyzed by real-time polymerase chain reaction and Western blotting.Compared to controls, telmisartan monotherapy had no significant influence on hydroxyproline; however, telmisartan plus propranolol reduced hydroxyproline (TP 3 months, p = 0.008), fibrosis score (TP 3 months and TP 8 months, p = 0.043 and p = 0.008, respectively; TP delayed 8 months, p0.0005), bile duct proliferation (TP 8 months and TP delayed 8 months, p = 0.006 and p0.0005, respectively), and procollagen α1(I), endothelin-1, TIMP-1 and MMP3 mRNA as well as α-SMA, CK-19, and TIMP-1 protein.Telmisartan plus propranolol reduces liver fibrosis and bile duct proliferation in the PSC-like Abcb4 (-/-) mouse model, even when started at late stages of fibrosis, and may thus represent a novel therapeutic option for cholestatic liver diseases such as PSC.

Supplemental Digital Content is available in the text, Acute upper gastrointestinal bleeding (UGIB) is the leading indication for emergency endoscopy. Scoring schemes have been developed for immediate risk stratification. However, most of these scores include endoscopic findings and are based on data from patients with nonvariceal bleeding. The aim of our study was to design a pre-endoscopic score for acute UGIB—including variceal bleeding—in order to identify high-risk patients requiring urgent clinical management. The scoring system was developed using a data set consisting of 586 patients with acute UGIB. These patients were identified from the emergency department as well as all inpatient services at the University Hospital of Cologne within a 2-year period (01/2007–12/2008). Further data from a cohort of 322 patients who presented to our endoscopy unit with acute UGIB in 2009 served for external/temporal validation. Clinical, laboratory, and endoscopic parameters, as well as further data on medical history and medication were retrospectively collected from the electronic clinical documentation system. A multivariable logistic regression was fitted to the development set to obtain a risk score using recurrent bleeding, need for intervention (angiography, surgery), or death within 30 days as a composite endpoint. Finally, the obtained risk score was evaluated on the validation set. Only C-reactive protein, white blood cells, alanine-aminotransferase, thrombocytes, creatinine, and hemoglobin were identified as significant predictors for the composite endpoint. Based on the regression coefficients of these variables, an easy-to-use point scoring scheme (C-WATCH) was derived to estimate the risk of complications from 3% to 86% with an area under the curve (AUC) of 0.723 in the development set and 0.704 in the validation set. In the validation set, no patient in the identified low-risk group (0–1 points), but 38.7% of patients in the high-risk group (≥ 2 points) reached the composite endpoint. Our easy-to-use scoring scheme is able to distinguish high-risk patients requiring urgent endoscopy, from low-risk cases who are suitable candidates for outpatient management or in whom endoscopy may be postponed. Based on our findings, a prospective validation of the C-WATCH score in different patient populations outside the university hospital setting seems warranted.

With great interest we have read the recent paper by Poh et al 1 suggesting the use of a routine parameter-based risk score for the development of hepatocellular carcinoma (HCC) in Asian patients with chronic HBV infection (CHBV). With an estimated 240 million people being chronically infected by HBV worldwide, CHBV is a major global health burden, putting these people at risk for the development of liver cirrhosis and HCC.2–4 It remains challenging to identify those patients with CHBV carrying a high risk for HCC development applying an easy to use, readily available and cost effective test system. Therefore risk predicting …

Since survival rates of fulminant liver failure are low, early consideration of liver transplantation in patients developing hepatic encephalopathy due to progressive liver failure is mandatory. Rapid diagnostic work-up is necessary to identify the underlying disease and to rule out contraindications to liver transplantation. We report the case of a 35-year-old patient presenting with fulminant hepatitis and a four-week history of biopsy-proven autoimmune hepatitis. Despite high-dose steroid-treatment liver function progressively worsened and hepatic encephalopathy rapidly developed. Histopathologic evaluation of a liver biopsy specimen revealed necrotizing hepatitis and rare atypical lymphocytes. Surgical biopsy specimens confirmed the suspicion of an aggressive hepatosplenic alphabeta T-cell lymphoma which represents a contraindication to liver transplantation.