Purpose Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Particularly morbidly obese patients are at risk of developing progressive liver disease. Nutritional and lifestyle intervention is recommended as the standard of care in NAFLD. However, there is a striking lack of evidence to support the efficacy of lifestyle intervention to treat NAFLD in morbidly obese patients. Here, we aimed to assess the impact of lifestyle intervention on NAFLD in the morbidly obese in a real-world setting. Methods 136 obese patients were included in an industry-independent, multiprofessional lifestyle intervention program with a lead-in phase of 12 weeks of formula diet and a total of 48 weeks intensive counselling. Body weight and markers of the metabolic syndrome were analyzed. Presence of NAFLD was screened for by use of non-invasive markers of fatty liver, non-alcoholic steatohepatitis and liver fibrosis. Results Weight loss goals (i.e. > 5% or > 10% of initial body weight, respectively, depending on baseline BMI) were achieved in 89.7% of subjects in the intention-to-treat analysis and 93.9% in the per-protocol analysis. This was associated with a pronounced improvement in serum ALT values. The percentage of subjects who fulfilled non-invasive criteria for fatty liver dropped from 95.2 to 54.8%. Risk of NASH improved and the number of patients at risk of liver fibrosis declined by 54.1%. Conclusion Lifestyle intervention was associated with a marked improvement of serum ALT and an improvement of surrogate scores indicative of NAFLD and, importantly, advanced fibrosis, in a real-world cohort of morbidly obese patients.

Aims In Europe, endoscopic submucosal dissection (ESD) is not yet the standard treatment for premalignant or early malignant lesions in the gastrointestinal (GI)-tract. High quality data is limited to single center studies. The German ESD registry was set up to evaluate and assess the technical success, curative resection rate, economic aspects as well as long term outcomes of ESD procedures performed in Germany. In this study, we present results of ESD procedures in Barrett’s esophagus (BE) from the German ESD registry.

Vanishing bile duct syndromes (VBDS) are characterized by progressive destruction of intrahepatic and sometimes extrahepatic branches of the biliary tree. A common symptom of all VBDS is chronic cholestasis, which is often progressive and leads to biliary cirrhosis and its sequelae. VBDS are heterogeneous in their etiology. The most common VBDS diseases in adults are primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). In children, biliary atresia, Byler's disease and Alagille syndrome classify as VBDS, but they are rare. Ursodeoxycholic acid (UDCA), a naturally occurring dihydroxy bile acid, is the only drug currently approved for the treatment of patients with PBC, and has been studied for several other cholestatic syndromes. Effectiveness of UDCA in patients with PBC has been shown. In addition, beneficial effects have also been observed in patients with other VBDS including PSC, cystic fibrosis and chronic graft-versus-host-disease (GVHD). Several potential mechanisms of action of UDCA have been proposed including biophysical effects and intracellular modulation of signaling events and secretion. Of these, cholangiocyte protection, stimulation of impaired hepatocellular secretion, and anti-apoptotic effects are probably the most relevant mechanisms currently under investigation.

Zusammenfassung Hintergrund Adipositas und die assoziierten Folgeerkrankungen führen nicht nur zu einer erhöhten Morbidität und Mortalität, sondern auch zu einer Reduktion der Lebensqualität. Obwohl ein multimodaler Therapieansatz die leitliniengerechte Therapie der Wahl für die meisten Patienten ist, fehlen in Deutschland flächendeckend geeignete Programme und die Ansprechraten unstrukturierter Interventionen sind unzureichend. Material und Methodik Das ZEPmax-Programm ist ein konservatives, multimodales, 1-jähriges Therapieprogramm mit initialer Formuladiätphase für Erwachsene mit Adipositas. Die Patienten treffen sich jede Woche für 3,5 Stunden am Zentrum. Die Daten der ersten 136 konsekutiv eingeschlossenen Patienten wurden hier als Intention-to-treat-Analyse ausgewertet. Neben Gewicht und BMI wurden Faktoren des metabolischen Syndroms untersucht. Ergebnisse Die Teilnehmer hatten einen durchschnittlichen BMI von 43,0 kg/m2. 11,8 % brachen das Programm im ersten Jahr ab. 87,5 % erreichten das primäre Therapieziel einer Gewichtsreduktion von > 10 % des Ausgangsgewichts bei einem durchschnittlichen Gewichtsverlust von 24,7 kg (19 % des Ausgangsgewichts). 72 % der Diabetespatienten (n = 18) erreichten eine vollständige Remission, d. h. einen normwertigen HbA1c ohne spezifische Diabetesmedikation. Der systolische Blutdruck der Hypertoniepatienten (n = 53) sank im Mittel um 22 mmHg. Das Gesamtcholesterin der Patienten mit Hyperlipidämie (n = 66) konnte um 23 mg/dl und das LDL-Cholesterin um 17 mg/dl gesenkt werden. Schlussfolgerung Die vorliegende Arbeit zeigt, dass mit Hilfe des strukturierten, formuladiätbasierten, multimodalen Adipositas-Therapieprogramms ZEPmax ein nachhaltiger Gewichtsverlust mit hohen Ansprechraten erreicht werden kann. Durch erfolgreiche Therapie der Adipositas konnten die assoziierten Folgeerkrankungen Diabetes mellitus Typ 2, arterielle Hypertonie und Hyperlipidämie mit hohen Remissionsquoten behandelt werden. Die vorliegende Arbeit belegt den Stellenwert einer professionell durchgeführten konservativen Adipositastherapie in Deutschland.

Background Obesity and related diseases are associated not only with an increased morbidity and mortality, but also with a reduced quality of life. Although a multimodal conservative therapy is recommended by guidelines, suitable programs are not offered nationwide in Germany and the response rates of unstructured interventions are insufficient. Material and Methods The ZEPmax-Program is a conservative, multimodal, one-year therapy program with an initial formula diet for adults with obesity. The patients meet once a week for 3,5 hours at the center. In all 136 patients were included in this evaluation. Besides weight and BMI also the factors of the metabolic syndrome were assessed in an Intention-to-treat analysis. Results The participants had an average BMI of 43,0 kg/m(2). 11,8% did not complete the one-year program. The patients lost 24,7 kilograms or respectively 19% of the initial weight and 87,5% reached the therapeutic goal of 10% relative weight loss. 72% of the patients with diabetes (n=18) achieved a complete remission with normal HbA1c and without medication. The systolic blood pressure of the patients with hypertension (n=53) dropped by 22mmHg. The cholesterol in patients with hyperlipidemia (n = 66) could be lowered by 23mg/dl and the LDL-Cholesterol by 17mg/dl. Conclusion This survey shows that a sustained weight loss with high response rates can be achieved with a structured, formuladiet-based multimodal obesity treatment program (ZEPmax). Obesity related diseases like diabetes, hypertension and hyperlipidemia could be treated with high remission rates by an effective treatment of obesity. This evaluation demonstrates the significance of a professionally conducted conservative obesity treatment in Germany.

Non-alcoholic fatty liver disease (NAFLD) is rising in prevalence, and a better pathophysiologic understanding of the transition to its inflammatory phenotype (NASH) is key to the development of effective therapies. To evaluate the contribution of the NLRP3 inflammasome and its downstream effectors IL-1 and IL-18 in this process, we applied the true-to-life “American lifestyle-induced obesity syndrome” (ALiOS) diet mouse model. Development of obesity, fatty liver and liver damage was investigated in mice fed for 24 weeks according to the ALiOS protocol. Lipidomic changes in mouse livers were compared to human NAFLD samples. Receptor knockout mice for IL-1 and IL-18 were used to dissect the impact of downstream signals of inflammasome activity on the development of NAFLD. The ALiOS diet induced obesity and liver steatosis. The lipidomic changes closely mimicked changes in human NAFLD. A pro-inflammatory gene expression pattern in liver tissue and increased serum liver transaminases indicated early liver damage in the absence of histological evidence of NASH. Mechanistically, Il-18r−/−- but not Il-1r−/− mice were protected from early liver damage, possibly due to silencing of the pro-inflammatory gene expression pattern. Our study identified NLRP3 activation and IL-18R-dependent signaling as potential modulators of early liver damage in NAFLD, preceding development of histologic NASH.

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/m2) 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/m2). 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 (NAS≤4) 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.

Aktuell stellt die endoskopische Submukosadissketion (ESD) noch kein Standardverfahren zur endoskopischen Therapie von prämalignen und frühmaligen Läsionen im Gastrointestinaltrakt dar. Ziel der ESD ist es, Läsionen en-bloc zu resezieren um eine histopathologisch klare Aussage hinsichtlich einer R0-Resektion sowie der Tiefeninfiltration treffen zu können. Aus Europa, Amerika oder Australien wurden bislang wenige Daten publiziert. Diese wurden zudem ausschließlich in single center Studien erhoben.

Zum aktuellen Zeitpunkt stellt die endoskopische Submukosadissektion (ESD) noch kein Standardverfahren zur Therapie von prämalignen und frühmalignen Läsionen im Gastrointestinaltrakt in Europa dar. Bislang beschränkten sich die publizierten Daten auf unizentrische Studien. Mit dem deutschen ESD-Register soll die ESD hinsichtlich des technischen Erfolges, der Kuration, der ökonomischen Aspekte und der Rezidivraten evaluiert werden.

In Europe, endoscopic submucosal dissection (ESD) is not yet the standard treatment for premalignant or early malignant lesions in the gastrointestinal (GI)-tract. High quality data is limited to single center studies. In this study, we present the first results of the German ESD registry which was set up to evaluate and assess the technical success, curative resection rate, economic aspects as well as long term outcomes of ESD procedures performed in Germany.

Western lifestyle-associated malnutrition causes steatosis that may progress to liver inflammation and mitochondrial dysfunction has been suggested as a key factor in promoting this disease. Here we have molecularly, biochemically and biophysically analyzed mitochondria from steatotic wild type and immune-compromised mice fed a Western diet (WD) - enriched in saturated fatty acids (SFAs). WD-mitochondria demonstrated lipidomic changes, a decreased mitochondrial ATP production capacity and a significant sensitivity to calcium. These changes preceded hepatocyte damage and were not associated with enhanced ROS production. Thus, WD-mitochondria do not promote steatohepatitis per se, but demonstrate bioenergetic deficits and increased sensitivity to stress signals.

Obeticholic acid (OCA), a potent farnesoid X receptor agonist, was studied as monotherapy in an international, randomized, double‐blind, placebo‐controlled phase 2 study in patients with primary biliary cholangitis who were then followed for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of ursodeoxycholic acid, which is relevant for patients who are intolerant of ursodeoxycholic acid and at higher risk of disease progression. Patients were randomized and dosed with placebo (n = 23), OCA 10 mg (n = 20), or OCA 50 mg (n = 16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing). The primary endpoint was the percent change in alkaline phosphatase from baseline to the end of the double‐blind phase of the study. Secondary and exploratory endpoints included change from baseline to month 3/early termination in markers of cholestasis, hepatocellular injury, and farnesoid X receptor activation. Efficacy and safety continue to be monitored through an ongoing 6‐year open‐label extension (N = 28). Alkaline phosphatase was reduced in both OCA groups (median% [Q1, Q3], OCA 10 mg −53.9% [−62.5, −29.3], OCA 50 mg −37.2% [−54.8, −24.6]) compared to placebo (−0.8% [−6.4, 8.7]; P < 0.0001) at the end of the study, with similar reductions observed through 6 years of open‐label extension treatment. OCA improved many secondary and exploratory endpoints (including γ‐glutamyl transpeptidase, alanine aminotransferase, conjugated bilirubin, and immunoglobulin M). Pruritus was the most common adverse event; 15% (OCA 10 mg) and 38% (OCA 50 mg) discontinued due to pruritus. Conclusion: OCA monotherapy significantly improved alkaline phosphatase and other biochemical markers predictive of improved long‐term clinical outcomes. Pruritus increased dose‐dependently with OCA treatment. Biochemical improvements were observed through 6 years of open‐label extension treatment. (Hepatology 2018;67:1890‐1902).

ObjectivePrimary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications.DesignWe collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes.ResultsWe identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10–9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region,RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells.ConclusionWe present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate geneRSPO3in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

The prevalence of obesity-related nonalcoholic fatty liver disease (NAFLD) is rising. NAFLD may result in nonalcoholic steatohepatitis (NASH), progressing to liver cirrhosis. Weight loss is recommended to treat obesity-related NASH. Lifestyle intervention may improve NASH; however, pertinent trials have so far focused on overweight patients, whereas patients with obesity are at highest risk of developing NAFLD. Furthermore, reports of effects on liver fibrosis are scarce. We evaluated the effect of lifestyle intervention on NAFLD in a real-life cohort of morbidly obese patients. In our observational study, 152 patients underwent lifestyle intervention, with a follow-up of 52 weeks. Noninvasive measures of obesity, metabolic syndrome, liver steatosis, liver damage, and liver fibrosis were analyzed. Treatment response in terms of weight loss was achieved in 85.1% of patients. Dysglycemia and dyslipidemia improved. The proportion of patients with fatty liver dropped from 98.1 to 54.3% ( P < 0.001). Weight loss >10% was associated with better treatment response ( P = 0.0009). Prevalence of abnormal serum transaminases fell from 81.0 to 50.5% ( P < 0.001). The proportion fibrotic patients, as determined by the NAFLD fibrosis score, dropped from 11.8 to 0% ( P < 0.05). Low serum levels of adiponectin correlated with degree of liver damage, i.e., serum liver transaminases ( r = -0,32, P < 0.05). Serum levels of adiponectin improved with intervention. In conclusion, lifestyle intervention effectively targeted obesity and the metabolic syndrome. Liver steatosis, damage and fibrosis were ameliorated in this real-life cohort of morbidly obese patients, mediated in part by changes in the adipokine profile. Patients with weight loss of >10% seemed to benefit most. NEW & NOTEWORTHY We demonstrate new evidence that lifestyle intervention is effective in treating NAFLD in the important group of patients with (morbid) obesity. Although current guidelines on the therapy of NASH recommend weight loss of 5-7%, weight reduction >10% may be favorable in morbid obesity. Serum levels of adipokines correlate with liver damage, which is indicative of their pathogenetic importance in human NASH. Our study adds to the limited body of evidence that NAFLD-associated liver fibrosis may resolve with lifestyle intervention.

Background & aims: Intrahepatic cholestasis of pregnancy (ICP) is defined by pruritus, elevated total fasting serum bile salts (TBS) and transaminases, and an increased risk of adverse fetal outcome. An accurate diagnostic marker is needed. Increased serum autotaxin correlates with cholestasis-associated pruritus. We aimed to unravel the diagnostic accuracy of autotaxin in ICP. Methods: Serum samples and placental tissue were collected from 44 women with uncomplicated pregnancies and 105 with pruritus and/or elevated serum transaminases. Autotaxin serum levels were quantified enzymatically and by western blotting, autotaxin gene expression by quantitative PCR. Results: Serum autotaxin was increased in ICP (mean ± SD: 43.5 ± 18.2nmol·mL-1·min-1, n=55, p<0.0001) compared to other pruritic disorders of pregnancy (16.8 ± 6.7nmol·mL-1·min-1, n=33), pre-eclampsia complicated by HELLP-syndrome (16.8 ± 8.9nmol·mL-1·min-1, n=17), and pregnant controls (19.6 ± 5.7nmol·mL-1·min-1, n=44). Longitudinal analysis during pregnancy revealed a marked rise in serum autotaxin with onset of ICP-related pruritus. Serum autotaxin was increased in women taking oral contraceptives. Increased serum autotaxin during ICP was not associated with increased autotaxin mRNA in placenta. With a cut-off value of 27.0nmol·mL-1 ·min-1, autotaxin had an excellent sensitivity and specificity in distinguishing ICP from other pruritic disorders or pre-eclampsia/HELLP-syndrome. Serum autotaxin displayed no circadian rhythm and was not influenced by food intake. Conclusions: Increased serum autotaxin activity represents a highly sensitive, specific and robust diagnostic marker of ICP distinguishing ICP from other pruritic disorders of pregnancy and pregnancy-related liver diseases. Pregnancy and oral contraception increase serum autotaxin to a much lesser extent than ICP. INTRODUCTION Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis, is a pregnancyspecific liver disorder with onset mainly in the third trimester of pregnancy. ICP is characterized by pruritus, elevated serum fasting bile salts and transaminases and an increased risk of adverse fetal outcomes.1-3 This disorder typically affects 0.2–2% of all pregnant women. The incidence of ICP, however, varies considerably with ethnicity and geographical location with the highest rates observed in Northern Europe and Southern America.2,4 Pruritus is the defining symptom of ICP, which progressively worsens as the pregnancy advances. Pruritus may considerably reduce quality of life, lead to sleep deprivation, depressed mood, and even suicidal ideation in more severe cases. In contrast to other more commonly observed pruritic dermatoses of pregnancy,5 a concern in ICP is the increased risk of adverse fetal outcomes.1,2 ICP increases the risk of fetal distress, cardiotocography abnormalities, preterm labor and sudden intrauterine death particularly in those women with total serum fasting bile salt (TBS) levels exceeding 40μmol/L.3,4,6,7 Therefore a proper diagnosis is essential to enable pharmacological treatment with ursodeoxycholic acid (UDCA), close antenatal monitoring and potentially the induction of labor after 37 weeks with the aim of reducing fetal distress and intrauterine death.8,9 The diagnosis of ICP is currently based on the presence of pruritus, raised fasting serum TBS levels above 10μmol/L, and/or elevated serum transaminases (in the absence of diseases that cause cholestasis or pruritus) as well as spontaneous relief of signs and symptoms within four to six weeks after delivery.1,10 However, diagnosis of ICP may be difficult when considering other pregnancy-associated dermatoses, liver diseases and their possible co-existence. The most sensitive marker for ICP is a raised fasting level of TBS while serum transaminases may be normal in up to 30% of cases.6,11 However, an asymptomatic elevation of TBS levels, hypercholanaemia, is observed in approximately 10% of pregnant women,12 and has been reported to affect up to 40% of Argentinean pregnancies.13 In addition, serum TBS increase upon food intake, thereby increasing variation unless serum is collected upon fasting. Elevated serum transaminases during the 3rd trimester of pregnancy are seen in women with HELLP-syndrome (hemolysis, elevated liver enzymes and low platelet count), pre-eclampsia, acute fatty liver of pregnancy and other non pregnancy-related liver disorders including obesity.1,2,6 These women also hold an increased risk for fetal adverse outcomes, but have an aetiology that differs from women with ICP. Furthermore, the management of these conditions is different from that of ICP. Autotaxin (ATX) is a lysophospholipase D which is essential for angiogenesis and neuronal development during embryogenesis.14 Other physiological functions attributed to ATX include cellular motility, proliferation, and lymphocyte homing.15 The effects of ATX are largely mediated by the enzymatic formation of lysophosphatidic acid (LPA) which may act via one of at least six different LPA receptors.14,16 ATX levels have been reported to be increased during pregnancy and correlate positively with gestational age.17 To identify the pruritogens of cholestasis we recently screened sera from ICP women for activation of neuronal cells and identified LPA as a potent neuronal activator.18 LPA and ATX levels were significantly increased in ICP women compared to gestation-matched pregnant controls. LPA could be related to pruritus during ICP as intradermal injection of LPA in mice caused a dose-dependent scratch response.18 AUTOTAXIN ACTIVITY HAS A HIGH ACCURACY TO DIAGNOSE ICP

Erhöhte Leberwerte werden oft zufällig bei Routine-Blutuntersuchungen entdeckt. Die Differenzialdiagnose ist umfangreich, die häufigsten Gründe sind hierzulande aber die nicht-alkoholische Fettlebererkrankung (NAFLD) oder der Alkoholabusus. Auch an eine chronische Hepatitis B oder C sollte man denken.

The data presented in this article describe the fatty acid composition of chow, liver tissue and isolated liver mitochondria from mice fed for 6–24 weeks with a high caloric western diet (WD) in comparison to control diet (normal diet, ND). The fatty acid composition was measured via gas chromatography flame ionization detection (GC-FID). Moreover, WD-induced mitochondrial protein changes are presented in this work and were analyzed by mass spectrometry (LC–MS/MS). For further interpretation and discussion of the presented data please refer to the research article entitled “Mitochondrial adaptation in steatotic mice” (Einer et al., 2017) [1].

Die Prävalenz der Adipositas beträgt in Deutschland ca. 25%. Komplikationen sind Diabetes mellitus und nicht-alkoholische Fettlebererkrankung (NAFLD), mit Progression zur Fettleberhepatitis (NASH) und Leberzirrhose. Pharmakologische Therapieoptionen fehlen. Leitlinien empfehlen zur Therapie der Adipositas multimodale Gewichtsreduktionsprogramme. Deren Effektivität zur Therapie der NAFLD ist wenig evaluiert und wurde hier untersucht.

Zusammenfassung Diese Leitlinie wurde unter Federführung der DGVS und mit Beteiligung benachbarter Fachgebiete erstellt und soll als praktische Hilfe für die Diagnostik und Therapie der Autoimmunen Lebererkrankungen dienen. Sie soll den aktuellen Stand der Wissenschaft darstellen, das Erkennen der Erkrankung fördern und die Behandlung der Patienten verbessern.