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Background Non-alcoholic fatty liver disease (NAFLD) affects more than 18 million individuals in Germany. Real-world data help to better characterize the natural history of disease and standard of care. Methods The German NAFLD-Registry is a prospective non-interventional study initiated by the German Liver Foundation and aims to describe clinical characteristics and observe outcomes in patients with NAFLD recruited in secondary and tertiary care. Results From this ongoing study, baseline data of the first 501 patients (mean age 54 years, 48% women) were analysed. 13 % of the study population had a high risk for advanced fibrosis (FIB-4 ≥2.67), approximately one-third had a liver stiffness value ≥9.6kPa measured by transient elastography, and the clinical diagnosis of liver cirrhosis was present in 10%. Typical comorbidities were more prevalent in high risk as compared to low risk patients (FIB-4 Conclusion First data of the German NAFLD registry show that approximately every 10th patient has advanced NAFLD, highlights T2DM patients as a high-risk group and gives insights in the use of comedication and life-style interventions in secondary and tertiary care.

Immunotherapy has become the standard of care in advanced HCC but is only approved in first- or second-line treatment. We report a patient with HCC refractory to several lines of tyrosine kinase inhibitors, who was treated with Ipilimumab and Nivolumab (Ipi/Nivo) as the fourth line. The tumor responded profoundly to Ipi/Nivo. Established biomarker-predicting responses to immunotherapy, such as a high PD-L1 staining, a high combined-positive score, microsatellite instability or a high tumor mutational burden, were not detected. Potential negative predictive markers for response to immunotherapy such as CTNNB1 and TERT were present. This constellation puts the spotlight on two mutations observed here in the SET domain-containing 2 (SETD2) and low-density lipoprotein receptor-related protein 1b (LRP1B) genes, which may explain the outstanding response. Our case demonstrates that immunotherapy can be efficient in a late-line scenario, resulting in long-term survival. Further studies should prospectively evaluate the value of SETD2 and LRP1B alterations as predictors for the success of immunotherapy in HCC.Die Immuntherapie wurde der Therapiestandard für die Behandlung des fortgeschrittenen HCC, ist allerdings nur in der Erst- oder Zweitlinie zugelassen. Wir berichten hier über einen Patienten mit HCC, der in einer TKI-refraktären Situation mit Ipi/Nivo in der Viertlinie therapiert wurde. Der Tumor sprach profunde auf die Therapie mit Ipi/Nivo an. Etablierte Biomarker, die ein Ansprechen auf eine Immuntherapie voraussagen können, wie eine hohe PD-L1-Expression, ein hoher

BACKGROUND & AIMS: The progression of nonalcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC.METHODS: C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH diets (for example, choline-deficient high-fat diet, CD-HFD) or chow diet for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a CD-HFD, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with NAFL, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and scRNA-Seq analysis were performed in liver and gastrointestinal tissue for immune cells in mice and humans.RESULTS: Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen-specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B-cells and showed a positive correlation between IgA levels and activated FcRγ+ hepatic myeloid cells as well extent of liver fibrosis.CONCLUSIONS: Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for treating NASH.IMPACT AND IMPLICATIONS: Nonalcoholic steatohepatitis (NASH) is a chronic inflammatory condition on the rise and can lead to hepatocellular carcinoma (HCC), the 3rd most common cause of cancer-related death worldwide. Currently, there is no effective treatment for this progressive disease that correlates with a marked risk of HCC mortality and carries a substantial healthcare burden. To date, among all the solid tumours, especially in HCC, the incidence and mortality rates are almost the same, making it crucial to find curative treatments for chronic diseases, such as NASH, which highly predispose to tumorigenesis. We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we could show that the absence of B cells prevented HCC development. B-cell intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets in combinatorial NASH therapies against inflammation and fibrosis.

Nonalcoholic fatty liver disease (NAFLD) represents an increasingly recognized disease entity with rising prevalence of 25% in the general population. Given the epidemic increase, regulatory agencies have defined an unmet medical need and implemented initiatives to expedite the development of drugs for NASH treatment.Literature search in Medline and worldwide web was accessed latest in 23.01.2021. In recent years new drugs acting on various pathophysiological processes in NASH have entered clinical development. These drugs combine beneficial metabolic effects with anti-inflammatory and anti-fibrotic effects to treat NASH. Current drug classes being investigated for NASH treatment are agonists of nuclear receptors such as FXR agonists (including FGF19), PPAR agonists, chemokine receptor inhibitors, thyroid hormone receptor-ß agonists and analogues of enterohepatic hormones including GLP-1 and FGF21 or SGLT2 inhibitors.Obeticholic acid is the only drug with significant benefit in the phase 3 interim results and remains the candidate for first conditional approval as a NASH therapeutic. However, monotherapy with these drugs leads to a histological resolution of NASH in less than one-third of patients in recent trials. Therefore, the future of NASH therapy will putatively be a combination therapy of two different drug classes with complementary effects.

Background: Non-alcoholic steatohepatitis (NASH) and fibrosis are the main prognostic factors in non-alcoholic fatty liver disease (NAFLD). The FIB-4 score has been suggested as an initial test for the exclusion of progressed fibrosis. However, increasing evidence suggests that also NASH patients with earlier fibrosis stages are at risk of disease progression, emphasizing the need for improved non-invasive risk stratification. Methods: We evaluated whether the apoptosis biomarker M30 can identify patients with fibrotic NASH despite low or intermediate FIB-4 values. Serum M30 levels were assessed by ELISA, and FIB-4 was calculated in an exploration (n = 103) and validation (n = 100) cohort of patients with histologically confirmed NAFLD. Results: The majority of patients with low FIB-4 (cut-off value < 1.3) in the exploration cohort revealed increased M30 levels (>200 U/L) and more than 80% of them had NASH, mostly with fibrosis. NASH was also detected in all patients with intermediate FIB-4 (1.3 to 2.67) and elevated M30, from which ~80% showed fibrosis. Importantly, in the absence of elevated M30, most patients with FIB-4 < 1.3 and NASH showed also no fibrosis. Similar results were obtained in the validation cohort. Conclusions: The combination of FIB-4 with M30 enables a more reliable identification of patients at risk for progressed NAFLD and might, therefore, improve patient stratification.

Doctor, Do You Know Red Yeast Rice?

Zusammenfassung. Wir stellen Fälle von Patientinnen und Patienten mit erhöhtem Gesamtcholesterin vor, die eine alternative Therapie zur herkömmlichen Medikation der Cholesterin-Senkung anwenden wollten. Bei allen Personen konnte eine Verbesserung des Lipidprofils festgestellt werden, wobei alle das aus Roter Reishefe hergestellte Produkt sehr gut vertragen haben. Nebenwirkungen konnten nicht festgestellt werden. Die Patientinnen und Patienten, die dieses Produkt aus rot fermentiertem Reis einnehmen, wählen bewusst ein alternatives Mittel aus dem Bereich der Phytotherapie, weil sie meist schon mehrere schulmedizinische Medikamente einnehmen müssen und nicht mehr bereit sind, ein weiteres Medikament dieser Art zu verwenden. Ein weiterer Grund ist, dass sie die Nebenwirkungen nicht mehr in Kauf nehmen möchten, unter denen sie bei der Einnahme eines gängigen Lipidsenkers gelitten haben.

Zusammenfassung. Wir berichten über einen 74-jährigen Mann, der plötzlich einschiessende und in der Folge zur Bettlägrigkeit führende lumbale Schmerzen spürte. Ein MRT zeigte die Progredienz einer bereits bekannten Spinalkanalstenose L2/3 mit aktivierten Osteochondrosen und Spondylarthrosen. Eine Facettengelenksinfiltration brachte keine Schmerzlinderung, ebenso wenig wie die Durchführung eines Sakralblocks. Bei persistierenden Schmerzen wurde die lumbale Operation geplant, vorgängig zur Operation bei Status nach Myokardinfarkt musste eine Koronar-CT durchgeführt werden. Bei Niereninsuffizienz war die Bestimmung des Kreatinins notwendig. Bei der Blutabnahme wurde zudem das CRP bestimmt, das erhöht war. Bei Verdacht auf das Vorliegen einer Prostatitis aufgrund des erhöhten PSA-Wertes wurde eine antibiotische Behandlung begonnen. Zwei Tage nach Beginn der Antibiose zeigte sich die Schmerzlinderung, und die Operation konnte abgesagt werden.

The incidence of non-alcoholic fatty liver disease (NAFLD) is rising, especially in Western countries. Drug treatment in patients with NAFLD is common since it is linked to other conditions like diabetes, obesity, and cardiovascular disease. Consequently, changes in drug metabolism may have serious clinical implications. Areas covered: A literature search for studies in animal models or patients with obesity, fatty liver, non-alcoholic steatohepatitis (NASH) or NASH cirrhosis published before November 2016 was performed. After discussing epidemiology and animal models for NAFLD, we summarized both basic as well as clinical studies investigating changes in drug transport and metabolism in NAFLD. Important drug groups were assessed separately with emphasis on clinical implications for drug treatment in patients with NAFLD. Expert opinion: Given the frequency of NAFLD even today, a high degree of drug treatment in NAFLD patients appears safe and well-tolerated despite considerable changes in hepatic uptake, distribution, metabolism and transport of drugs in these patients. NASH causes changes in biliary excretion, systemic concentrations, and renal handling of drugs leading to alterations in drug efficacy or toxicity under specific circumstances. Future clinical drug studies should focus on this special patient population in order to avoid serious adverse events in NAFLD patients.

Nonalcoholic fatty liver disease (NAFLD) is increasing globally with an estimated prevalence of approximately 25 %. Nonalcoholic steatohepatitis as the progressive disease entity often leads to fibrosis and end-stage disease. The magnitude of NAFLD patients are not diagnosed and have no access to further clinical assessment. Diagnostic pathways for individual risk evaluation fitting with available resources are of utmost importance in real-world clinical practice. Retrospective analysis of 1346 anonymized outpatient datasets at Würzburg University Hospital, Germany. Transient elastography (TE) with controlled attenuation parameter and laboratory-based risk scores (NFS, FIB-4) were the main diagnostic workup tools for risk stratification. After preselection based on questionnaire information NAFLD still accounts for one-fifth of patients in the liver outpatient service. More than 80 % of NAFLD patients receive their first-time diagnosis in our unit. Laboratory-based risk scores and TE are valuable tools for second-step risk assessment as shown in our clinical data analysis. Moreover, 65 % of NAFLD patients use inpatient services for at least 1 day. The policy to perform liver biopsy in high-risk patients above the recommended threshold of 9.6 kPa if any clinical doubt exists regarding the diagnosis of cirrhosis leads to a histological down staging in almost 80 %. Questionnaire-based referral from primary care followed by broadly available fast-track TE and eventually liver biopsy for selected patients is the standard practice in our unit. This approach represents a feasible model to handle the large gap between availability and clinical need for TE facilities.EINFüHRUNG UND ZIELSETZUNG: Die nichtalkoholische Fettlebererkrankung (NAFLD) nimmt weltweit zu und erreicht mittlerweile eine Prävalenz von etwa 25 %. Die nichtalkoholische Steatohepatitis (NASH) als fortschreitende Erkrankungsentität führt oft zur Fibrose bis hin zur Zirrhose. Die Mehrheit der NAFLD-Patienten wird weder diagnostiziert, noch haben sie Zugang zu weiteren medizinischen Maßnahmen. Diagnostische Algorithmen zur individuellen Risikoabschätzung, die mit den verfügbaren Ressourcen vereinbar sind, werden im klinischen Ambulanzalltag dringlich benötigt. Es wurde eine retrospektive Analyse von 1346 anonymisierten Ambulanzdatensätzen am Universitätsklinikum Würzburg durchgeführt. Die transiente Elastografie (TE) mit Controlled Attenuation Parameter (CAP) und laborbasierten Risikoscores (NFS, FIB-4) wurde als primäres Diagnoseverfahren zur Risikostratifizierung eingesetzt. Nach Präselektion basierend auf einem Zuweisungsfragebogen umfasst die NAFLD ein Fünftel der Patienten in der Leberambulanz. Über 80 % der NAFLD-Patienten erhalten die erstmalige Diagnose in unserer Abteilung. Laborbasierte Risikoscores und eine breit verfügbare TE sind dabei hilfreiche Methoden der weiterführenden Risikoabschätzung. 65 % der NAFLD-Patienten werden im Verlauf für mindestens einen Tag hospitalisiert. Die Strategie, eine Leberbiopsie bei Hochrisikopatienten über dem Grenzwert von 9,6 kPa durchzuführen, wenn klinisch Zweifel an der Diagnose einer Zirrhose bestehen, führt bei nahezu 80 % zur histologischen Herabstufung des Fibrosegrades. Die auf einem Zuweisungsfragebogen basierende Vorstellung von Patienten aus der Primärversorgung zur breit und rasch verfügbaren TE ist das Standardvorgehen in unserer Abteilung. Für selektionierte Patienten folgt im Einzelfall eine direkt veranlasste Leberbiopsie. Diese Vorgehensweise hat sich als hilfreich erwiesen, um die Lücke zwischen Bedarf und Verfügbarkeit an weiterführender NAFLD-Diagnostik inklusive ambulanter TE zu schließen.

OBJECTIVES: Nonalcoholic steatohepatitis (NASH) and fibrosis play critical roles for the prognosis of patients with nonalcoholic fatty liver disease (NAFLD). Identification of patients at risk of NASH and fibrosis is therefore critical for disease management. NAFLD Fibrosis Score (NFS) and transient elastography (TE) have been suggested to exclude advanced fibrosis. However, there is increasing evidence that also patients with NASH and early fibrosis are at risk of disease progression and complications, emphasizing the need for improved noninvasive risk stratification in NAFLD. METHODS: Because hepatocyte apoptosis plays an early role in NASH pathogenesis, we evaluated whether the apoptosis biomarker M30 might identify NAFLD patients who are at risk of NASH and fibrosis despite low NFS or TE values. Serum M30 levels were assessed by enzyme-linked immunosorbent assay in combination with NFS and/or TE in an exploration (n = 103) and validation (n = 100) cohort of patients with biopsy-proven NAFLD. RESULTS: Most patients with low NFS (cutoff value < −1.455) revealed increased M30 levels (>200 U/L) in the exploration (62%) and validation (67%) cohort, and more than 70% of them had NASH, mostly with histological fibrosis. Vice versa, most patients with NFS < −1.455 but nonelevated M30 levels showed no NASH. NASH was also detected in most patients with indeterminate NFS (−1.455 to 0.676) but elevated M30 levels, from which ∼90% showed fibrosis. Similar results were obtained when using TE instead of NFS. DISCUSSION: The combination of the M30 biomarker with NFS or TE enables a more reliable identification of patients with an increased risk of progressed NAFLD and improves patient stratification.

Background & aims Current non-invasive scores for the assessment of severity of non-alcoholic fatty liver disease (NAFLD) and identification of patients with non-alcoholic steatohepatitis (NASH) have insufficient performance to be included in clinical routine. In the current study, we developed a novel machine learning approach to overcome the caveats of existing approaches. Methods Non-invasive parameters were selected by an ensemble feature selection (EFS) from a retrospectively collected training cohort of 164 obese individuals (age: 43.5±10.3y; BMI: 54.1 ±10.1kg/m ² ) to develop a model able to predict the histological assessed NAFLD activity score (NAS). The model was evaluated in an independent validation cohort (122 patients, age: 45.2±11.75y, BMI: 50.8±8.61kg/m ² ). Results EFS identified age, γGT, HbA1c, adiponectin, and M30 as being highly associated with NAFLD. The model reached a Spearman correlation coefficient with the NAS of 0.46 in the training cohort and was able to differentiate between NAFL (NAS4) and NASH (NAS>4) with an AUC of 0.73. In the independent validation cohort, an AUC of 0.7 was achieved for this separation. We further analyzed the potential of the new model for disease monitoring in an obese cohort of 38 patients under lifestyle intervention for one year. While all patients lost weight under intervention, increasing scores were observed in 15 patients. Increasing scores were associated with significantly lower absolute weight loss, lower reduction of waist circumference and basal metabolic rate. Conclusions A newly developed model (http://CHek.heiderlab.de) can predict presence or absence of NASH with reasonable performance. The new score could be used to detect NASH and monitor disease progression or therapy response to weight loss interventions. CA extern

Prevalence of non-alcoholic fatty liver disease is rising in the Western world and reaches up to 90% in patients undergoing bariatric surgery. Fibroscan(®) as a non-invasive tool for liver stiffness measurement (LSM) has several limitations in morbidly obese patients. Only few data exist about the technical feasibility and accuracy of LSM in these patients. We aimed to analyse the feasibility of LSM by Fibroscan(®) in bariatric patients.In morbidly obese patients, LSM was performed using XL probe. Measurements were termed reliable if 10 successful measurements with a success rate ≥60% and an interquartile range/median (IQR/M)0.3 were obtained, unreliable if 10 successful measurements were obtained but the IQR/M was0.3, and they were termed failed if they were neither reliable nor unreliable.A total of 149 patients were included (87 with liver biopsies); mean BMI was 51.6 ± 8.5 kg/m(2). In 41% LSM using XL-probe was reliable, in 22% unreliable and in 37% failed. Failed LSM was significantly more frequent in patients with higher BMI compared to reliable and unreliable measurements (p 0.05). In patients with failed measurement, sonographic paramedian and intercostal distances were significantly higher compared to reliable measurements. All three patients with F4 fibrosis could successfully be differentiated by LSM from patients without fibrosis.LSM with XL probe is feasible in almost two-thirds of morbidly obese patients with a BMI ≥50 kg/m(2). Reliable prediction of advanced fibrosis appears to be possible even if formal criteria of successful measurements are not met.

Nonalcoholic fatty liver disease is increasing in prevalence. It can be subdivided into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Five to twenty percent of cases progress from NAFL to NASH. Increased hepatic Th17 cells and IL-17 expression were observed in NASH mice and patients, respectively. We analyzed CD4+ effector T cells and regulatory T cells (Tregs) from peripheral blood and livers of NAFL and NASH patients. A total of 51 NAFL patients, 30 NASH patients, 31 nonalcoholic fatty liver disease patients (without histology), and 43 healthy controls were included. FACS analysis was performed on PBMCs and intrahepatic lymphocytes. Compared with healthy controls, a lower frequency of resting Tregs (rTregs; CD4+CD45RA+CD25++) and higher frequencies of IFN-γ+ and/or IL-4+ cells were detected among CD4+ T cells of peripheral blood in NASH, and to a lesser degree in NAFL. In hepatic tissue, NAFL to NASH progression was marked by an increase in IL-17+ cells among intrahepatic CD4+ T cells. To define immunological parameters in peripheral blood to distinguish NAFL from NASH, we calculated different ratios. Th17/rTreg and Th2/rTreg ratios were significantly increased in NASH versus NAFL. The relevance of our findings for NASH pathogenesis was highlighted by the normalization of all of the changes 1 y after bariatric surgery. In conclusion, our data indicate that NAFL patients show changes in their immune cell profile compared with healthy controls. NAFL to NASH progression is marked by an increased frequency of IL-17+ cells among intrahepatic CD4+ T cells and higher Th17/rTreg and Th2/rTreg ratios in peripheral blood.

Non-alcoholic fatty liver disease (NAFLD) represents an increasingly recognized disease entity with rising prevalence about 25% in the general population [1]. Given a substantial liver-related and ...

The gut-derived hormone fibroblast growth factor 15/19 (FGF15/19) is an emerging versatile regulator of various metabolic pathways. As such, FGF15/19 has been implicated in homeostatic control of bile acid, carbohydrate and lipid metabolism in multiple target organs including the liver, adipose tissue and brain. In line with this, growing evidence suggests that dysregulation of FGF15/19 contributes to a number of metabolic and bile acid-associated disorders such as fatty liver disease, Type 2 diabetes and different gastrointestinal dysfunctions. In this review we summarize the current knowledge on the organ-specific functions of FGF15/19 and address their underlying molecular mechanisms. Moreover, recent advances in the characterization of factors that control the release of the hormone in the gut will be discussed and linked to the current view of how alterations of FGF15/19 signaling may contribute to disease development. Finally, the suitability of FGF15/19 as a potential therapeutic target will be critically reviewed.

Die nicht-alkoholische Fettlebererkrankung (NAFLD) ist die haufigste chronische Lebererkrankung in Europa und den USA mit steigender Pravalenz. Eine hohe Pravalenz der NAFLD haben insbesondere Risikopatienten mit einem metabolischen Syndrom (Diabetes mellitus Typ 2, Adipositas, Hyperlipdamie). Aus einer blanden Lebersteatose (NAFL) kann sich in 5–20 % der Falle eine nicht-alkoholische Steatohepatitis (NASH) entwickeln, die zu einer Leberfibrose und -zirrhose fortschreiten kann. Im klinischen Alltag mussen Patienten mit einer NASH oder einer relevanten Fibrosierung identifiziert werden, denn diese Patienten haben eine erhohte Mortalitat im Vergleich zur Normalbevolkerung. Eine etablierte medikamentose Therapie der NASH steht aktuell nicht zur Verfugung. Deshalb steht die Therapie des metabolischen Syndroms und der Risikofaktoren bei Patienten mit NAFLD im Vordergrund.

Einleitung: Die nicht alkoholische Fettlebererkrankung (non-alcoholic fatty liver disease, NAFLD) stellt heutzutage in der westlichen Welt die haufigste Ursache einer chronischen Lebererkrankung dar. In der europaischen und US-amerikanischen Bevolkerung liegt die Pravalenz bei bis zu 30 %. Unklar ist die Versorgungssituation deutscher Fettleberpatienten. Methoden: An samtliche universitaren Leberzentren in Deutschland (n = 34) wurden Fragebogen (11 Fragen) zur Versorgungssituation der NAFLD-Patienten verschickt. Gefragt wurde u. a. nach dem Anteil von Fettleberpatienten in den Hochschulambulanzen, metabolischen Begleiterkrankungen und der Art der Zuweisung. Auch wurden die klinikinternen Standards erfasst. Hierbei wurden die Situationen von 2008 und 2013 miteinander verglichen. Ergebnisse: Die Rucklaufquote betrug 65 % (n = 22). Es zeigte sich, dass der Anteil von Fettleberpatienten in den Leberambulanzen zwischen 2008 und 2013 gestiegen war, wobei der uberwiegende Anteil von Patienten in den meisten Zentren von extern und nicht aus der eigenen Klinik uberwiesen worden war. Nur wenige Patienten wurden einem Diabetologen oder Endokrinologen vorgestellt, andererseits wurden aber durch die meisten Leberambulanzen Stoffwechselstorungen abgeklart. Nur gering ausgepragt war die Zusammenarbeit zwischen den Leberambulanzen und anderen Fachdisziplinen, diese wurde nur als mittelmasig bewertet, gemeinsame Besprechungen wurden nur selten abgehalten. Verlaufskontrollen der Patienten finden in allen Zentren regelmasig statt, allerdings nach unterschiedlichen Kriterien. Ein einheitlicher Algorithmus zur Risikobeurteilung und invasiven Diagnostik existiert nicht. Schlussfolgerung: Das Problembewusstsein um NAFLD-Patienten scheint in den letzten Jahren gestiegen zu sein. Dennoch ist die Betreuung dieser Patienten heterogen, einheitliche Standards existieren nicht. Eine gemeinsame Leitlinie ist daher dringend erforderlich.

Non-alcoholic fatty liver disease (NAFLD) is frequent among obese individuals with metabolic syndrome. Variants PNPLA3 p.I148M, TM6SF2 p.E167K and MBOAT7 rs641738 are associated with higher liver fat contents. Here we analyzed 63 biopsied non-obese, non-diabetic patients with NAFLD (39 men, age: 20-72 years) recruited within the German NAFLD CSG program. The frequencies of the PNPLA3, TM6SF2 and MBOAT7 polymorphisms were compared with the remaining patients in the NAFLD CSG cohort and with a control population (n = 174). Serum CK18-M30 was measured by ELISA. In non-obese NAFLD patients, the frequency of the PNPLA3 p.I148M allele (74.6%), but not of the TM6SF2 or MBOAT7 polymorphisms, was significantly (P < 0.05) higher as compared to the other patients in the NAFLD CSG cohort (54.9%) or controls (40.2%). The presence of the minor PNPLA3 p.I148M risk allele increased the risk of developing NAFLD (OR = 3.29, P < 0.001) and was associated with higher steatosis, fibrosis, and serum CK18-M30 levels (all P < 0.05). According to the population attributable fraction (PAF), 49.8% of NAFLD cases could be eliminated if the PNPLA3 mutation was absent. The MBOAT7 polymorphism was more frequent (P = 0.019) in patients with severe hepatic steatosis. In conclusion, PNPLA3, and to a lesser extent, MBOAT7 variants are associated with NAFLD risk and modulate liver injury in non-obese patients without diabetes.

Zusammenfassung. Wir berichten über eine 33-jährige Patientin, die sich 14 Tage nach Brustaugmentation mit Schmerzen im linken Oberarm und mit Sensibilitätseinschränkungen in der Handinnenseite links in der hausärztlichen Praxis vorstellt. Im Labor fanden sich erhöhte Werte für D-Dimere. In der Duplexsonografie lag eine ausgeprägte Thrombophlebitis der Vena basilica links vor. Nach Gabe von Rivaroxaban (Xarelto®) für vier Wochen und des Tragens eines Kompressionsverbands kam es zu einer Regredienz der Beschwerden. Fünf Wochen nach Diagnosestellung war die V. basilica links wieder rekanalisiert.

Background & Aims There is a growing evidence that bile acids are involved in the regulation of triglyceride-, cholesterol-homoeostasis and fat absorption. In this study organ-specific Fxr knockout mice were used to further investigate the influence of farnesoid X receptor FXR in lipogenesis. Methods Liver- and intestine-specific Fxr knockout mice were fed a 1% cholesterol diet for 28 days. Histological examination of frozen tissue sections included Sudan III/H&E, BODIPY staining and liver X receptor (LXR) immunohistochemistry. Liver triglycerides, serum cholesterol, serum bile acids and nuclear LXR protein were measured. mRNA expression of several genes involved in bile acid-, cholesterol-homoeostasis and lipogenesis was quantified by real-time PCR. Results Hepatic FXR deficiency contributes to lipid accumulation under 1% cholesterol administration which is not observed in intestinal Fxr knockout mice. Strong lipid accumulation, characterized by larger vacuoles could be observed in hepatic Fxr knockout sections, while intestinal Fxr knockout mice show no histological difference to controls. In addition, these mice have the ability to maintain normal serum cholesterol and bile acid levels. Hepatic Fxr knockouts were characterized by elevated triglycerides and bile acid levels. Expression level of LXR was significantly elevated under control and 1% cholesterol diet in hepatic Fxr knockout mice and was followed by concomitant lipogenic target gene induction such as Fas and Scd-1. This protective FXR effect against hepatic lipid accumulation was independent of intestinal Fgf15 induction. Conclusion These results show that the principal site of protective bile acid signalling against lipid accumulation is located in the liver since the absence of hepatic but not intestinal FXR contributes to lipid accumulation under cholesterol diet.

BACKGROUND: Fibroblast growth factor (FGF) 15/19 is part of the gut-liver crosstalk accounting for bile acid (BA) metabolism regulation. Dysregulation of fibroblast growth factor 15/19 signaling is observed in different pathological conditions, for example, in gastrointestinal diseases such as inflammatory bowel disease (IBD). To understand the molecular bases, we analyzed the enterohepatic regulation of Fgf15-mediated pathway in 2 different inflammatory bowel disease mouse models. METHODS: Target genes of the BA-farnesoid-X-receptor (Fxr)-Ffg15 axis were quantified by RT-PCR or western blotting in gut and liver of dextran sulfate sodium (DSS)-treated and IL10 mice. Serum Fgf15 levels were analyzed by ELISA. Biliary and fecal BA composition was differentiated by HPLC-MS/MS. RESULTS: Dextran sulfate sodium-treated mice with ileum-sparing colitis showed higher Fgf15 serum levels. In contrast, IL10 mice with ileitis had a trend toward decreased Fgf15 serum levels compared with controls and increased expression of Asbt as a negative Fxr-target gene. In hepatic tissue of both models, no histological changes, but higher interleukin 6 (IL-6) mRNA expression and down-regulation of Fxr and Cytochrom P450 7a1 mRNA expression were observed. Fibroblast growth factor receptor 4 up-regulation was in line with higher Fgf15 serum levels in dextran sulfate sodium-treated mice. A distinct fecal BA profile was observed in both models with significantly higher levels of taurine-conjugated BA in particular tauro-β-muricholic acid in IL10 mice. CONCLUSIONS: Ileum-sparing colitis is characterized by activation of Fxr-Fgf15 signaling with higher expression of Fxr-target gene Fgf15, whereas ileal inflammation showed no signs of Fxr-Fgf15 activation. Abundance of BA such as T-β-MCA may be important for intestinal Fxr activation in mice.

Non-alcoholic fatty liver (NAFL) disease is defined by an accumulation of liver fat exceeding 5% of its weight in the absence of significant alcoholic intake. In 5-20%, there is a progression from NAFL to non-alcoholic steatohepatitis (NASH). Until now, it is not well understood why only some patients develop NASH, and currently, no drugs are licensed for this indication. Different T-cell populations such as T-regulatory, Th1 and Th17 cells play a central role in the immunopathogenesis of fatty liver disease and open the option of future interleukin (IL)-17-based therapeutics. The inflammatory process underlying NASH is furthermore characterized by elevated expression of pro-inflammatory cytokines such as TNFα and IL-1β. Anakinra, a recombinant version of IL-1Ra shows promising metabolic effects with improved hyperglycemia and beta-cell secretory function in a double-blind placebo controlled randomized trial in type 2 diabetic patients but such studies are still in their preliminary stages for NASH. Several studies point out that bile acid farnesoid X receptor (FXR)-mediated signals (such as the enterohepatic hormone fibroblast growth factor 15/19) are involved in the regulation of triglyceride and glucose metabolism. Recent clinical trials have revealed a beneficial impact of the FXR agonist obeticholic acid on body weight, insulin sensitivity and liver histology in patients with NASH. Further potential novel therapeutic targets in NASH are currently in phase II clinical development.