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In this cross-sectional study, we hypothesized that a high dietary ratio of omega-6 (n-6) to omega-3 (n-3) fatty acids could be associated with an altered gut bacterial composition and with the disease severity in patients with nonalcoholic fatty liver disease (NAFLD). A total of 101 NAFLD patients were included in the study, of which 63 underwent a liver biopsy. All 101 patients completed a 14-day food and activity record. Ebispro 2016 professional software was used to calculate individual macronutrients and micronutrients consumed. Patients were grouped into 3 quantiles (Q) according to a low (Q1:6.1, n = 34), moderate (Q2: 6.1-7.8, n = 33), or high (Q3:7.8, n = 34) dietary n-6/n-3 ratio. Stool samples were analyzed using 16S rRNA gene sequencing. Spearman correlation coefficients and principal coordinate analysis were used to detect differences in the bacterial composition of the gut microbiota. The median dietary n-6/n-3 ratio of all patients was 6.7 (range, 3.1-14.9). No significant associations between the dietary n-6/n-3 ratio and the gut microbiota composition or disease severity were observed. However, the abundance of specific bacteria such as Catenibacterium or Lactobacillus ruminis were found to be positively correlated and the abundance of Clostridium were negatively correlated with dietary n-6 fatty acid intake. The results indicate that a high dietary n-6/n-3 ratio is probably not a highly relevant factor in the pathogenesis of human NAFLD. Further studies are needed to clarify the importance of interactions between gut bacterial taxa and n-6 fatty acids in the pathophysiology of NAFLD.

Purpose of Review Patients with non-alcoholic fatty liver disease (NAFLD), often considered as the hepatic manifestation of the metabolic syndrome, represent a population at high cardiovascular risk and frequently suffer from atherogenic dyslipidemia. This article reviews the pathogenic interrelationship between NAFLD and dyslipidemia, elucidates underlying pathophysiological mechanisms and focuses on management approaches for dyslipidemic patients with NAFLD. Recent Findings Atherogenic dyslipidemia in patients with NAFLD results from hepatic and peripheral insulin resistance along with associated alterations of hepatic glucose and lipoprotein metabolism, gut dysbiosis, and genetic factors. Summary Since atherogenic dyslipidemia and NAFLD share a bi-directional relationship and are both major driving forces of atherosclerotic cardiovascular disease (ASCVD) development, early detection and adequate treatment are warranted. Thus, integrative screening and management programs are urgently needed. A stepwise approach for dyslipidemic patients with NAFLD includes (i) characterization of dyslipidemia phenotype, (ii) individual risk stratification, (iii) definition of treatment targets, (iv) lifestyle modification, and (v) pharmacotherapy if indicated.

Background & aimsStudies investigating the gut-liver axis have largely focused on bacteria, whereas little is known about commensal fungi. We characterized fecal fungi in patients with non-alcoholic fatty liver disease (NAFLD) and investigated their role in a fecal microbiome-humanized mouse model of Western diet-induced steatohepatitis.MethodsWe performed fungal internal transcribed spacer 2 sequencing using fecal samples from 78 patients with NAFLD, 16 controls and 73 patients with alcohol use disorder. Anti-Candida albicans (C.albicans) IgG was measured in blood samples from 17 controls and 79 patients with NAFLD. Songbird, a novel multinominal regression tool, was used to investigate mycobiome changes. Germ-free mice were colonized with feces from patients with non-alcoholic steatohepatitis (NASH), fed a Western diet for 20 weeks and treated with the antifungal amphotericin B.ResultsThe presence of non-obese NASH or F2-F4 fibrosis was associated with a distinct fecal mycobiome signature. Changes were characterized by an increased log-ratio for Mucor sp./Saccharomyces cerevisiae (S. cerevisiae) in patients with NASH and F2-F4 fibrosis. The C.albicans/S. cerevisiae log-ratio was significantly higher in non-obese patients with NASH when compared with non-obese patients with NAFL or controls. We observed a different fecal mycobiome composition in patients with NAFLD and advanced fibrosis compared to those with alcohol use disorder and advanced fibrosis. Plasma anti-C.albicans IgG was increased in patients with NAFLD and advanced fibrosis. Gnotobiotic mice, colonized with human NASH feces and treated with amphotericin B were protected from Western diet-induced steatohepatitis.ConclusionsNon-obese patients with NAFLD and more advanced disease have a different fecal mycobiome composition to those with mild disease. Antifungal treatment ameliorates diet-induced steatohepatitis in mice. Intestinal fungi could be an attractive target to attenuate NASH.Lay summaryNon-alcoholic fatty liver disease is one of the most common chronic liver diseases and is associated with changes in the fecal bacterial microbiome. We show that patients with non-alcoholic fatty liver disease and more severe disease stages have a specific composition of fecal fungi and an increased systemic immune response to Candida albicans. In a fecal microbiome-humanized mouse model of Western diet-induced steatohepatitis, we show that treatment with antifungals reduces liver damage.

Background and Aims: Hepatocellular carcinoma (HCC) surveillance in patients at risk is strongly recommended and usually performed by ultrasound (US) semiannually with or without alfa-fetoprotein (AFP) measurements. Quality pa-rameters except for surveillance intervals have not been strictly defined. We aimed to evaluate surveillance success and risk factors for surveillance failure. Methods: Patients with ≥1 US prior to HCC diagnosis performed at four tertiary referral hospitals in Germany between 2008 and 2019 were retrospectively analyzed. Surveillance success was defined as HCC detection within Milan criteria. Results: Only 47% of 156 patients, median age 63 (interquartile range: 57–70) years, 56% male, and 96% with cirrhosis, received recommended surveillance modality and interval. Surveillance failure occurred in 29% and was significantly associated with lower median model for end-stage liver disease (MELD) score odds ratio (OR) 1.154, 95% confidence interval (CI): 1.027– 1.297, p=0.025) and HCC localization within right liver lobe (OR: 6.083, 95% CI: 1.303–28.407, p=0.022), but not with AFP ≥200 µg/L. Patients with surveillance failure had significantly more intermediate/advanced tumor stages (93% vs. 6%, p

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

Maternal obesity predisposes for hepato-metabolic disorders early in life. However, the underlying mechanisms causing early onset dysfunction of the liver and metabolism remain elusive. Since obesity is associated with subacute chronic inflammation and accelerated aging, we test the hypothesis whether maternal obesity induces aging processes in the developing liver and determines thereby hepatic growth. To this end, maternal obesity was induced with high-fat diet (HFD) in C57BL/6N mice and male offspring were studied at the end of the lactation [postnatal day 21 (P21)]. Maternal obesity induced an obese body composition with metabolic inflammation and a marked hepatic growth restriction in the male offspring at P21. Proteomic and molecular analyses revealed three interrelated mechanisms that might account for the impaired hepatic growth pattern, indicating prematurely induced aging processes: (1) Increased DNA damage response (γH2AX), (2) significant upregulation of hepatocellular senescence markers (Cdnk1a, Cdkn2a); and (3) inhibition of hepatic insulin/insulin-like growth factor (IGF)-1-AKT-p38-FoxO1 signaling with an insufficient proliferative growth response. In conclusion, our murine data demonstrate that perinatal obesity induces an obese body composition in male offspring with hepatic growth restriction through a possible premature hepatic aging that is indicated by a pathologic sequence of inflammation, DNA damage, senescence, and signs of a possibly insufficient regenerative capacity.

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.

Introduction: Use of risk scores for early assessment of patients with upper gastrointestinal bleeding (UGIB) is recommended by various guidelines. We compared Cologne-WATCH (C-WATCH) score with Glasgow-Blatchford score (GBS), Rockall score (RS), and pre-endoscopic RS (p-RS). Methods: Patients with UGIB between January and December 2017 were retrospectively analyzed for 30-day mortality and composite endpoints risk of complications and need for intervention using areas under the receiver-operating characteristics curve (AUROC). Subgroup analysis was conducted for patients with UGIB on admission and in-hospital UGIB. Results: A total of 252 patients were identified (67.5% men, mean age 63.8 ± 14.9 years). In-hospital UGIB occurred in 49.6%. AUROCs for 30-day mortality, risk of complications, and need for intervention (not applicable to RS) were 0.684 (95% confidence interval [CI]: 0.606–0.763), 0.665 (95% CI: 0.594–0.735), and 0.694 (95% CI: 0.612–0.775) for C-WATCH score, 0.724 (95% CI: 0.653–0.796) and 0.751 (95% CI: 0.687–0.815) for RS, 0.652 (95% CI: 0.57–0.735), 0.653 (95% CI: 0.579–0.727), and 0.673 (95% CI: 0.602–0.745) for p-RS and 0.652 (95% CI: 0.572–0.732), 0.663 (95% CI: 0.592–0.734), and 0.752 (95% CI: 0.683–0.821) for GBS. RS outperformed pre-endoscopic scores in predicting risk of complications, while there were no significant differences between pre-endoscopic scores except GBS outperforming p-RS in predicting need for intervention. The subgroup analysis obtained similar results. Positive predictive values for patients with estimated low risk for all three endpoints (C-WATCH score ≤1, RS ≤2, p-RS Conclusion: C-WATCH score performed similar to the established pre-endoscopic risk scores in patients with UGIB regarding relevant patient-related endpoints with no significant differences between both the subgroups.

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.

A cirrhotic cardiomyopathy (CCM) can be observed in patients with end-stage liver disease and is characterized by a systolic and/or diastolic dysfunction in the absence of pre-existing heart diseases. While the cardiac dysfunction is often masked at rest, it typically manifests itself during cardiovascular challenges such as hypovolemia, physical stress, or sepsis. The diagnosis of CCM is challenging and predominantly based on echocardiographic measurements to identify subclinical cardiac dysfunction. Additional diagnostic criteria include electrophysiological abnormalities such as QT-interval prolongation, an abnormal chronotropic or inotropic response to stress, elevated cardiac biomarkers such as natriuretic peptides, and structural cardiac abnormalities like left atrium enlargement. There is no specific therapy for CCM. Supportive measures and regular cardiac evaluation of high-risk patients and transplant candidates are important to reduce the risks associated with invasive procedures and treatments.

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.

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.

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.

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.

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.

Cardiogenic shock is a life-threatening condition that is frequently associated with acute hepatic dysfunction. Due to low cardiac output resulting in end-organ hypoperfusion and hypoxia, different types of liver dysfunction can develop, such as hypoxic hepatitis or acute liver failure. A very serious and late sequela is the secondary sclerosing cholangitis in critically patients. Clinical management of acute hepatic dysfunction involves the stabilization of cardiac output to improve hepatic perfusion and the optimization of liver oxygenation. However, despite maximum efforts in supportive treatment, the outcome of patients with cardiogenic shock and concomitant hepatic dysfunction remains poor.

Aging, physical activity, bodyweight and diet are well established risk factors for cardiovascular disease. For all of these factors a great impact on the intestinal microbiome has been described. The current review will discuss available data regarding the role of the gut microbiome in regulating blood pressure, vascular function and its possible contribution to atherosclerosis and heart failure.

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.