Zusammenfassung Ziel Sowohl Über- als auch Unterernährung spielen für die Prognose von Patienten mit Leberkrankheiten eine bedeutende Rolle. Bei chronischer Leberkrankheit besteht häufig eine Mangelernährung mit gestörter Körperzusammensetzung, allerdings zeigt sich in den letzten Jahren ein Wandel des klinischen Spektrums mit Zunahme von Adipositas und sarkopener Adipositas. In der klinischen Praxis wird das Potenzial der Ernährungstherapie als metabolisches Management einer Leberkrankheit oft unterschätzt und nicht ausgeschöpft. Mit der Aktualisierung dieser Leitlinie sollen umfassende aktuelle und evidenzbasierte Empfehlungen für die Ernährungstherapie von Patienten mit Lebererkrankungen gegeben werden. Methoden Frühere Leitlinien der Deutschen und der Europäischen Gesellschaften für Ernährungsmedizin (DGEM, ESPEN) zur Ernährung von Patienten mit Lebererkrankungen wurden entsprechend den Prinzipien der AWMF (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften) und ÄZQ (Ärztliche Zentralstelle für Qualitätssicherung) aktualisiert und vollständig überarbeitet und erweitert. Ergebnisse Die vorliegende Leitlinie umfasst 110 im Konsentierungsverfahren ermittelte Aussagen und Empfehlungen zum ernährungsmedizinischen metabolischen Management leberkranker Patienten im Hinblick auf pathophysiologische Grundlagen, Indikationsstellung und Durchführung einer Ernährungstherapie sowie ihrer Ergebnisse. Empfehlungen werden für die Krankheitsbilder akutes Leberversagen (ALV), alkoholassoziierte Lebererkrankung (ALD), metabolische Dysfunktion-assoziierte Fettleberkrankheit (MASLD), Leberzirrhose (LZ), Lebertransplantation und Operation sowie ernährungsbedingte Leberschädigung (NALI) gegeben. Schlussfolgerung Bei Patienten mit chronischer Lebererkrankung liegt häufig ein prognostisch ungünstiger metabolischer Status vor mit gestörter Körperzusammensetzung und Mangelernährung oder Adipositas; diese Patientengruppe profitiert von einem evidenzbasierten ernährungsmedizinischen metabolischen Management. Bei Patienten mit akutem Leberversagen ist die Datenlage wesentlich unsicherer, da nur wenige Studiendaten für diese schwere, aber seltene Erkrankung vorliegen.

Aim Overnutrition as well as undernutrition have a major prognostic role for patients suffering from liver disease. In chronic liver disease, impaired body composition and malnutrition are common findings. In recent years, however, the clinical presentation has changed with an increasing proportion of obese and sarcopenic obese liver patients. More often than not the potential of metabolic management by nutrition support remains unrecognized and underused. The current update of this guideline is aimed at giving comprehensive, up-to-date and evidence-based recommendations for nutrition therapy in patients with liver disease. Methods Previous guidelines of the German and European Societies for Nutritional Medicine (DGEM, ESPEN) on nutrition in patients with liver disease were updated and thoroughly revised and extended according to the requirements of the AWMF (German Association of the Scientific Medical Societies) and the & Auml;ZQ (Agency for Quality in Medicine). Results The present guideline comprises 110 statements and recommendations developed in a consensus process on the nutritional metabolic management of patients with liver disease with regard to pathophysiological principles, indication for and application of nutritional therapy and the resulting outcome. Recommendations address the following conditions: acute liver failure, alcohol-associated liver disease, metabolic dysfunction-associated liver disease, liver cirrhosis, liver transplantation and surgery, as well as nutrition associated liver injury. Conclusions Patients with chronic liver disease frequently exhibit an unfavourable nutritional metabolic status with impaired body composition and malnutrition or obesity; this group of patients benefits from evidence based nutritional metabolic management. For patients with acute liver failure evidence is weak because there is only few data from studies in this severe but rare condition.

Introduction Whether regular moderate alcohol consumption does pose a severely increased risk to a healthy person is still heavily discussed. However, gender-specific limits for daily alcohol consumption have been lowered recently. The positive effect of alcohol-free beer drinks as alternatives to classic beer has not yet been proven. In this monocentric, randomized, multi-arm study, we investigated the influence of various non-alcoholic beer beverages [pilsner (PI), wheat beer (WB), mixed drink/Radler (MD), and water (WA)] as control, on fatty degeneration and damage to the liver, glucose and lipid metabolism.

IntroductionHepatic lipid accumulation and mitochondrial dysfunction are hallmarks of metabolic associated fatty liver disease (MAFLD), yet molecular parameters underlying MAFLD progression are not well understood. Differential methylation within the mitochondrial DNA (mtDNA) has been suggested to be associated with dysfunctional mitochondria, also during progression to Metabolic Steatohepatitis (MeSH). This study further investigates whether mtDNA methylation is associated with hepatic lipid accumulation and MAFLD. MethodsHepG2 cells were constructed to stably express mitochondria-targeted viral and prokaryotic cytosine DNA methyltransferases (mtM.CviPI or mtM.SssI for GpC or CpG methylation, respectively). A catalytically inactive variant (mtM.CviPI-Mut) was constructed as a control. Mouse and human patients' samples were also investigated. mtDNA methylation was assessed by pyro- or nanopore sequencing. Results and discussionDifferentially induced mtDNA hypermethylation impaired mitochondrial gene expression and metabolic activity in HepG2-mtM.CviPI and HepG2-mtM.SssI cells and was associated with increased lipid accumulation, when compared to the controls. To test whether lipid accumulation causes mtDNA methylation, HepG2 cells were subjected to 1 or 2 weeks of fatty acid treatment, but no clear differences in mtDNA methylation were detected. In contrast, hepatic Nd6 mitochondrial gene body cytosine methylation and Nd6 gene expression were increased in mice fed a high-fat high cholesterol diet (HFC for 6 or 20 weeks), when compared to controls, while mtDNA content was unchanged. For patients with simple steatosis, a higher ND6 methylation was confirmed using Methylation Specific PCR, but no additional distinctive cytosines could be identified using pyrosequencing. This study warrants further investigation into a role for mtDNA methylation in promoting mitochondrial dysfunction and impaired lipid metabolism in MAFLD.

Einleitung Die Menge an Alkohol, welche ohne Schädigung der Leber konsumiert werden kann, ist ein aktuelles Diskussionsthema. Der geschlechtsspezifische Grenzwert für den täglichen Alkoholkonsum wurden zuletzt weiter gesenkt. Alkoholfreie Alternativen zum Bier werden häufig beworben, jedoch fehlen Daten über die Auswirkungen von alkoholfreiem Bier auf den Metabolismus und mögliche Leberschädigungen.

Introduction Recent data indicate that hepatic steatosis is higher in patients with inflammatory bowel disease (IBD), including ulcerative colitis (UC). We have recently shown that TNFα treatment is associated with lower rates of steatosis in patients with Crohn's disease compared to controls. This could be related to a reduction of IBD-specific risk factors like intestinal inflammation. This study aimed to examine the hepatic status in patients with UC compared to patients with IBS who lack intestinal inflammation.

Background: Acute liver failure (ALF) occurs as a rare, sudden, extensive loss of liver function in a previously healthy liver. In advanced cases, ALF may require liver transplantation (LT). Available prognostic parameters have limited accuracy to decide, which patient to consider for LT. The liver maximum function capacity test (LiMAx) can accurately determine liver function and was assessed as predictor of survival, along with coagulation parameters and liver stiffness in nonacetaminophen-induced ALF. Methods: Various liver function tests, including LiMAx measurements, coagulation factors, and transient elastography (TE), were analyzed retrospectively for associations with clinical outcome in 34 patients with ALF or acute hepatitis (AH). Data were compared between patients with spontaneous recovery (SR) and non-SR (3-month mortality/LT; NSR). Results: The analysis included 34 patients (22 ALF, 12 AH; 19 males, 15 females; age 36.7 ± 14.6 years) with drug-induced liver injury (DILI) (n = 12), autoimmune hepatitis (AIH; n = 13), AIH-DILI overlap (n = 1), viral (n = 9), or cryptogenic liver failure (n = 1). Thirty-one patients recovered spontaneously, 2 patients died, and 1 patient underwent LT. The LiMAx was 197.6 (±68.4) for SR versus 92.33 (±65.0) for NSR (p = 0.0157). Fibrinogen was significantly lower in patients with NSR than in SR patients (209.0 vs. 106.3; p = 0.02). Mean liver stiffness measured by TE was 39.3 for NSR and 17.3 for SR (p = 0.26). KCC was fulfilled in only 4 patients (3 SR, 1 NSR). LiMAx results correlated positively with serum fibrinogen and antithrombin III concentrations and correlated negatively with liver stiffness. No other analyzed factor could differentiate between SR and NSR. Conclusion: Decision-making in ALF remains challenging. LiMAx and fibrinogen might predict the prognosis in patients with nonacetaminophen-induced ALF and in combination could be feasible tools to decide if LT is necessary.

Background: Nonalcoholic fatty liver disease (NAFLD) is a disease characterized by lipid accumulation within hepatocytes, ranging from simple steatosis to steatohepatitis, in the absence of secondary causes of hepatic fat accumulation. Although air pollution (AP) has been associated with several conditions related to NAFLD (e.g., metabolic syndrome, type 2 diabetes mellitus), few studies have explored an association between AP and NAFLD. The aim of the study was to investigate whether exposure to AP is associated with NAFLD prevalence. Methods: We used baseline cross-sectional data (2000–2003) of the Heinz–Nixdorf–Recall cohort study in Germany (baseline n = 4,814), a prospective population-based cohort study in the urbanized Ruhr Area. Mean annual exposure to size-fractioned particulate matter (PM10, PM2.5, PMcoarse, and PM2.5abs), nitrogen dioxide, and particle number was assessed using two different exposure models: a chemistry transport dispersion model, which captures urban background AP exposure on a 1 km2 grid at participant’s residential addresses, and a land use regression model, which captures point-specific AP exposure at participant’s residential addresses. NAFLD was assessed with the fatty liver index (n = 4,065), with NAFLD defined as fatty liver index ≥60. We estimated ORs of NAFLD per interquartile range of exposure using logistic regression, adjusted for socio-demographic and lifestyle variables. Results: We observed a NAFLD prevalence of 31.7% (n = 1,288). All air pollutants were positively associated with NAFLD prevalence, with an OR per interquartile range for PM2.5 of 1.11 (95% confidence interval [CI] = 1.00, 1.24) using chemistry transport model, and 1.06 (95% CI = 0.94, 1.19) using the land use regression model, respectively. Conclusion: There was a positive association between long-term AP exposure and NAFLD.

The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is increasing rapidly worldwide due to the obesity epidemic. Advanced stages of the MAFLD, such as non-alcoholic steatohepatitis (NASH) with advanced fibrosis or cirrhosis are affecting global health. Extracellular vesicles (EVs) are released by all cell types and are important in cell-to-cell communication and maintaining homeostasis, but they also play a role in the pathogenesis of various diseases. EVs contain biological information such as lipids, proteins, messenger RNAs (mRNAs), small RNAs, and DNA, and they act on (distant) target cells. The cargo of EVs is dependent on the type and the state of the releasing cell. EVs have been proposed as biomarkers, prognostic, and even therapeutic agents, also in the context of liver diseases. This review aims to give an overview of the current knowledge on EVs in MAFLD, including the role and interaction of EVs with different cell types in the liver. Several aspects of EVs, including their origin, characteristics, cargo, and functions are reviewed. Moreover, the potential of EVs as targets for the treatment of MAFLD is discussed.

Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) have emerged as leading causes of chronic liver diseases worldwide. ALD and NAFLD share several pathophysiological patterns as well as histological features, while clinically, they are distinguished by the amount of alcohol consumed daily. However, NAFLD coexists with moderate alcohol consumption in a growing proportion of the population. Here, we investigated the effects of moderate alcohol consumption on liver injury, lipid metabolism, and gut microbiota in 30 NAFLD-patients. We anonymously assessed drinking habits, applying the AUDIT- and CAGE-questionnaires and compared subgroups of abstainers vs. low to harmful alcohol consumers (AUDIT) and Cage 0–1 vs. Cage 2–4. Patients who did not drink any alcohol had lower levels of γGT, ALT, triglycerides, and total cholesterol. While the abundance of Bacteroidaceae, Bifidobacteriaceae, Streptococcaceae, and Ruminococcaceae was higher in the low to harmful alcohol drinking cohort, the abundance of Rikenellaceae was higher in the abstainers. Our study suggests that even moderate alcohol consumption has an impact on the liver and lipid metabolism, as well as on the composition of gut microbiota.

Background and Aims: Radioembolization (RE) has recently demonstrated a non-inferior survival outcome compared to systemic therapy for advanced hepatocellular carcinoma (HCC). Therefore, current guidelines recommend RE for patients with advanced HCC and preserved liver function who are unsuitable for transarterial chemoembolization (TACE) or systemic therapy. However, despite the excellent safety profile of RE, post-therapeutic hepatic decompensation remains a serious complication that is difficult to predicted by standard laboratory liver function parameters or imaging modalities. LiMAx® is a non-invasive test for liver function assessment, measuring the maximum metabolic capacity for 13C-Methacetin by the liver-specific enzyme CYP 450 1A2. Our study investigates the potential of LiMAx® for predicting post-interventional decompensation of liver function. Patients and methods: In total, 50 patients with HCC with or without liver cirrhosis and not amenable to TACE or systemic treatments were included in the study. For patients prospectively enrolled in our study, LiMAx® was carried out one day before RE (baseline) and 28 and 90 days after RE. Established liver function parameters were assessed at baseline, day 28, and day 90 after RE. The relationship between baseline LiMAx® and pre-and post-interventional liver function parameters, as well as the ability of LiMAx® to predict hepatic decompensation, were analyzed. Results: We observed a strong association between baseline LiMAx® and bilirubin, albumin, ALBI grade, and MELD score. Patients presenting with Child–Pugh score B 28 days after RE or with a deterioration in Child–Pugh score by at least one point had a significantly lower baseline LiMAx® compared to those with Child–Pugh score A or with stable Child–Pugh score. The ability of LiMAx® to predict hepatic decompensation after RE was determined using ROC curve analysis and was compared to MELD score and ALBI grade. LiMAx® achieved a substantial AUC of 0.8117, comparable to MELD score and ALBI grade. Conclusion: Patients with lower LiMAx® values at baseline have a significantly increased risk for hepatic decompensation after RE, despite being categorized as Child–Pugh A. Therefore, LiMAx® can be used as an additional tool to identify patients at high risk of post-interventional hepatic failure.

Celiac disease (CeD) is a chronic autoimmune disorder characterized by an intolerance to storage proteins of many grains. CeD is frequently associated with liver damage and steatosis. Bile acid (BA) signaling has been identified as an important mediator in gut–liver interaction and the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here, we aimed to analyze BA signaling and liver injury in CeD patients. Therefore, we analyzed data of 20 CeD patients on a gluten-free diet compared to 20 healthy controls (HC). We furthermore analyzed transaminase levels, markers of cell death, BA, and fatty acid metabolism. Hepatic steatosis was determined via transient elastography, by MRI and non-invasive scores. In CeD, we observed an increase of the apoptosis marker M30 and more hepatic steatosis as compared to HC. Fibroblast growth factor 19 (FGF19) was repressed in CeD, while low levels were associated with steatosis, especially in patients with high levels of anti-tissue transglutaminase antibodies (anti-tTG). When comparing anti-tTG-positive CeD patients to individuals without detectable anti-tTG levels, hepatic steatosis was accentuated. CeD patients with significant sonographic steatosis (defined by CAP ≥ 283 db/m) were exclusively anti-tTG-positive. In summary, our results suggest that even in CeD patients in clinical remission under gluten-free diet, alterations in gut–liver axis, especially BA signaling, might contribute to steatotic liver injury and should be further addressed in future studies and clinical practice.

High-calorie diets lead to hepatic steatosis and to the development of non-alcoholic fatty liver disease (NAFLD), which can evolve over many years into the inflammatory form of non-alcoholic steatohepatitis (NASH), posing a risk for the development of hepatocellular carcinoma (HCC). Due to diet and liver alteration, the axis between liver and gut is disturbed, resulting in gut microbiome alterations. Consequently, detecting these gut microbiome alterations represents a promising strategy for early NASH and HCC detection. We analyzed medical parameters and the fecal metaproteome of 19 healthy controls, 32 NASH patients, and 29 HCC patients, targeting the discovery of diagnostic biomarkers. Here, NASH and HCC resulted in increased inflammation status and shifts within the composition of the gut microbiome. An increased abundance of kielin/chordin, E3 ubiquitin ligase, and nucleophosmin 1 represented valuable fecal biomarkers, indicating disease-related changes in the liver. Although a single biomarker failed to separate NASH and HCC, machine learning-based classification algorithms provided an 86% accuracy in distinguishing between controls, NASH, and HCC. Fecal metaproteomics enables early detection of NASH and HCC by providing single biomarkers and machine learning-based metaprotein panels.

Background Religious fasting during the holy month of Ramadan requires abstaining from food and liquids. It is allowed to consume food and drinks from dusk till dawn. In the summer month, fasting can be regarded as a modified form of intermittent fasting, resulting in reduced and timed calorie intake. Type 2 diabetes (TD2) is a risk factor for developing non-alcoholic steatohepatitis (NASH). Several studies suggested some benefits of interval fasting for TD2 and NASH patients. Here we aimed to characterize the impact of a one-month fasting period on glucose and lipid metabolism liver health in a cohort of T2D patients.

The fasting month of Ramadan can be regarded as a modified form of interval fasting. However, in contrast to the usual recommendations, religious fasting in this form also requires abstaining from liquids during the day, while food being consumed in defined periods after sunset, generally resulting in a reduced and timed intake of total calories. Type 2 diabetes (T2D) is associated with non-alcoholic fatty liver disease (NAFLD). The aim of this study was to characterize the impact of a one-month interval fasting period on liver health, glucose and lipid metabolism in a cohort of T2D patients. Patients’ blood samples were collected at the beginning and end of the four-week fasting period. The status of the liver was examined by fibroscan including measurement of the controlled attenuation parameter (CAP). Following the fasting period, the patients experienced a significant weight loss. While fibroscan (8.0±1.2 vs. 8.6±1.6 before/after fasting) and CAP (311.4±9.6 vs. 302.6 ±10.4 before/after fasting) showed modest changes, transaminase levels and the apoptosis marker M30 as well as adiponectin were significantly decreased after fasting. Serum levels of triglycerides were significantly decreased after the interval fasting. Glucose levels did not change significantly but serum levels of C-peptide and insulin increased following the interval fasting period. In this cohort of T2D patients, we demonstrated that a 4-week intermittent fasting period resulted in an improvement in different serum parameters associated with glucose, liver, and lipid metabolism.

HepatoBiliary Surg Nutr 2022;11(2):299-301 | https://dx.doi.org/10.21037/hbsn-21-548 In 2019, metabolic dysfunction-associated fatty liver disease (MAFLD) was introduced as a novel definition in order to represent the causal etiologies (i.e., overweight, type 2 diabetes, metabolic syndrome) of the majority of patients with fatty liver disease without discrimination for chronic alcohol consumption, as non-alcoholic fatty liver disease (NAFLD) became the leading cause of chronic injury in western societies (1). NAFLD diagnosis is based on the detection of hepatic steatosis with exclusion of any secondary causality, especially chronic harmful alcohol ingestion. Unlike NAFLD, MAFLD definition requires invasive or non-invasive hepatic steatosis assessment in addition to being overweight/obese, and/or type 2 diabetes and/or the presence of two metabolic dysfunction criteria without the exclusion of other liver diseases. Therefore, MAFLD and NAFLD do not reflect the same patient population. While MAFLD includes any patient with relevant metabolic risk factors and steatosis regardless of additional causes, NAFLD includes a significant number of patients without metabolic risk factors (lean NAFLD). However, to date there is little data available on the impact of the modified definition on clinical outcome and associated mortality, as previously discussed elsewhere (2). With great interest we read the original article by Kim et al. focusing on the differences between MAFLD and NAFLD regarding cardiovascular, cancer-related, and allcause mortality (3). Unfortunately, the authors did not have access to liver-related mortality data nor differentiate into different cancer types (i.e., hepatic vs. extrahepatic). However, in a nested analysis of the NHANES III cohort, representing 7,761 individuals, Kim et al. clearly demonstrated that MAFLD was associated with significantly higher all-cause mortality (HR =1.17; 95% CI: 1.04–1.32). In contrast, individuals that were declared as NAFLD following ultrasound diagnosis of steatosis and exclusion of harmful alcohol intake and viral hepatitis B or C had no significant increase in all-cause mortality after multivariate analysis and adjustment for metabolic risk factors. Indeed, advanced fibrosis in MAFLD, as estimated by NAFLD fibrosis score, FIB-4 or APRI resulted in an even higher risk for all-cause mortality (HR =2.0; 95% CI: 1.49–2.69), while in NAFLD, individuals with advanced fibrosis remained at a non-significant level of all-cause mortality (HR =1.45; 95% CI: 0.95–2.21). Looking at specific causes, cancer-related mortality was associated with MAFLD (HR =1.95; 95% CI: 1.05–3.62), but not with NAFLD. A recent meta-analysis revealed that MAFLD and NAFLD overlapped at a rate of 81.59% (CI: 66.51– Editorial

OBJECTIVES:Lately, many countries have restricted or even banned transfat, and palm oil has become a preferred replacement for food manufacturers. Whether palm oil is potentially an unhealthy food mainly due to its high content of saturated Palmitic Acid (PA) is a matter of debate. The aim of this study was to test whether qualitative aspects of diet such as levels of PA and the fat source are risk factors for Metabolic Syndrome (MS) and Metabolic Associated Fatty Liver Disease (MAFLD).METHODS:C57BL/6 male mice were fed for 14 weeks with three types of Western diet (WD): 1. LP-WD-low concentration of PA (main fat source-corn and soybean oils); 2. HP-WD-high concentration of PA (main fat source-palm oil); 3. HP-Trans-WD-high concentration of PA (mainly transfat).RESULTS:All types of WD caused weight gain, adipocyte enlargement, hepatomegaly, lipid metabolism alterations, and steatohepatitis. Feeding with HP diets led to more prominent obesity, hypercholesterolemia, stronger hepatic injury, and fibrosis. Only the feeding with HP-Trans-WD resulted in glucose intolerance and elevation of serum transaminases. Brief withdrawal of WDs reversed MS and signs of MAFLD. However, mild hepatic inflammation was still detectable in HP groups.CONCLUSIONS:HP and HP-Trans-WD play a crucial role in the genesis of MS and MAFLD.