Publications by authors named "Jörn M Schattenberg"

128 Publications

NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

Authors:
Dominik Pfister Nicolás Gonzalo Núñez Roser Pinyol Olivier Govaere Matthias Pinter Marta Szydlowska Revant Gupta Mengjie Qiu Aleksandra Deczkowska Assaf Weiner Florian Müller Ankit Sinha Ekaterina Friebel Thomas Engleitner Daniela Lenggenhager Anja Moncsek Danijela Heide Kristin Stirm Jan Kosla Eleni Kotsiliti Valentina Leone Michael Dudek Suhail Yousuf Donato Inverso Indrabahadur Singh Ana Teijeiro Florian Castet Carla Montironi Philipp K Haber Dina Tiniakos Pierre Bedossa Simon Cockell Ramy Younes Michele Vacca Fabio Marra Jörn M Schattenberg Michael Allison Elisabetta Bugianesi Vlad Ratziu Tiziana Pressiani Antonio D'Alessio Nicola Personeni Lorenza Rimassa Ann K Daly Bernhard Scheiner Katharina Pomej Martha M Kirstein Arndt Vogel Markus Peck-Radosavljevic Florian Hucke Fabian Finkelmeier Oliver Waidmann Jörg Trojan Kornelius Schulze Henning Wege Sandra Koch Arndt Weinmann Marco Bueter Fabian Rössler Alexander Siebenhüner Sara De Dosso Jan-Philipp Mallm Viktor Umansky Manfred Jugold Tom Luedde Andrea Schietinger Peter Schirmacher Brinda Emu Hellmut G Augustin Adrian Billeter Beat Müller-Stich Hiroto Kikuchi Dan G Duda Fabian Kütting Dirk-Thomas Waldschmidt Matthias Philip Ebert Nuh Rahbari Henrik E Mei Axel Ronald Schulz Marc Ringelhan Nisar Malek Stephan Spahn Michael Bitzer Marina Ruiz de Galarreta Amaia Lujambio Jean-Francois Dufour Thomas U Marron Ahmed Kaseb Masatoshi Kudo Yi-Hsiang Huang Nabil Djouder Katharina Wolter Lars Zender Parice N Marche Thomas Decaens David J Pinato Roland Rad Joachim C Mertens Achim Weber Kristian Unger Felix Meissner Susanne Roth Zuzana Macek Jilkova Manfred Claassen Quentin M Anstee Ido Amit Percy Knolle Burkhard Becher Josep M Llovet Mathias Heikenwalder

Nature 2021 Apr 24;592(7854):450-456. Epub 2021 Mar 24.

Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need. Here we report the progressive accumulation of exhausted, unconventionally activated CD8PD1 T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8PD1 T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8PD1CXCR6, TOX, and TNF T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8 T cells or TNF neutralization, suggesting that CD8 T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8PD1 T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.
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http://dx.doi.org/10.1038/s41586-021-03362-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046670PMC
April 2021

Editorial: the polygenic risk of cirrhosis development.

Aliment Pharmacol Ther 2021 04;53(7):849-850

Department of Medicine, University Medical Center Mainz Department of Internal Medicine 1, Mainz, Germany.

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http://dx.doi.org/10.1111/apt.16298DOI Listing
April 2021

Development of a novel machine learning model to predict presence of nonalcoholic steatohepatitis.

J Am Med Inform Assoc 2021 Mar 4. Epub 2021 Mar 4.

Metabolic Liver Research Program. I. Department of Medicine, University Medical Center, Mainz, Germany.

Objective: To develop a computer model to predict patients with nonalcoholic steatohepatitis (NASH) using machine learning (ML).

Materials And Methods: This retrospective study utilized two databases: a) the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) nonalcoholic fatty liver disease (NAFLD) adult database (2004-2009), and b) the Optum® de-identified Electronic Health Record dataset (2007-2018), a real-world dataset representative of common electronic health records in the United States. We developed an ML model to predict NASH, using confirmed NASH and non-NASH based on liver histology results in the NIDDK dataset to train the model.

Results: Models were trained and tested on NIDDK NAFLD data (704 patients) and the best-performing models evaluated on Optum data (~3,000,000 patients). An eXtreme Gradient Boosting model (XGBoost) consisting of 14 features exhibited high performance as measured by area under the curve (0.82), sensitivity (81%), and precision (81%) in predicting NASH. Slightly reduced performance was observed with an abbreviated feature set of 5 variables (0.79, 80%, 80%, respectively). The full model demonstrated good performance (AUC 0.76) to predict NASH in Optum data.

Discussion: The proposed model, named NASHmap, is the first ML model developed with confirmed NASH and non-NASH cases as determined through liver biopsy and validated on a large, real-world patient dataset. Both the 14 and 5-feature versions exhibit high performance.

Conclusion: The NASHmap model is a convenient and high performing tool that could be used to identify patients likely to have NASH in clinical settings, allowing better patient management and optimal allocation of clinical resources.
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http://dx.doi.org/10.1093/jamia/ocab003DOI Listing
March 2021

Impact of Non-Alcoholic Fatty Liver Disease on Metabolic Comorbidities in Type 2 Diabetes Mellitus.

Exp Clin Endocrinol Diabetes 2021 Feb 18. Epub 2021 Feb 18.

Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

Objective: Type 2 Diabetes (T2D) is a major risk factor for the development and progression of non-alcoholic fatty liver disease (NAFLD). The published prevelance in epidemiological studies in this high risk population exceeds 70%. The aim of this analysis was to investigate the impact of NAFLD on T2D patients in Germany.

Methods: Using the Disease Analyzer Database (IQVIA), T2D patients with NAFLD diagnosed in Germany were matched to a cohort without NAFLD controlling for age, sex, physician, index year and metabolic comorbidities and assessed for their risk of developing myocardial infarction, stroke, peripheral arterial disease (PAD) or chronic kidney disease, as well as the type of T2D treatment on NAFLD.

Results: 2633 T2D patients with NAFLD were matched to 2633 T2D patients without liver disease. The ICD coded prevalence of NAFLD in patients with T2D in primary care in Germany was 7.8%. On regression analysis of patients with T2D , the presence of NAFLD was associated with a higher risk of renal failure during follow-up (HR 1.17, 95% CI 1.02-1.34, p=0.027). No association with the development of myocardial infarction, stroke, PAD or initiation of insulin therapy was observed. NAFLD patients were more frequently treated with DDP-4 inhibitors (+/-metformin) and less frequently with insulin within the first year of T2D diagnosis. The metabolic control (HbA1c range 6.5-7.5%) during follow-up did not differ between both groups.

Conclusion: The coded prevalence of NAFLD in T2D patients is low, which is in contrast to published series. Enhancing disease awareness of NAFLD and screening recommendations in high risk populations will be beneficial for the active management of these patients.
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http://dx.doi.org/10.1055/a-1378-4679DOI Listing
February 2021

Disease burden and economic impact of diagnosed non-alcoholic steatohepatitis in five European countries in 2018: A cost-of-illness analysis.

Liver Int 2021 Feb 15. Epub 2021 Feb 15.

Hôpital de la Pitié-Salpêtrière, Paris, France.

Background And Aims: Non-alcoholic steatohepatitis (NASH) is a chronic disease that can progress to end-stage liver disease (ESLD). A large proportion of early-stage NASH patients remain undiagnosed compared to those with advanced fibrosis, who are more likely to receive disease management interventions. This study estimated the disease burden and economic impact of diagnosed NASH in the adult population of France, Germany, Italy, Spain and the United Kingdom in 2018.

Methods: The socioeconomic burden of diagnosed NASH was estimated using cost-of-illness methodology applying a prevalence approach to estimate the number of adults with NASH and the attributable economic and wellbeing costs. Given undiagnosed patients do not incur costs in the study, the probability of diagnosis is central to cost estimation. The analysis was based on a literature review, databases and consultation with clinical experts, economists and patient groups.

Results: The proportion of adult NASH patients with a diagnosis ranged from 11.9% to 12.7% across countries, which increased to 38.8%-39.1% for advanced fibrosis (F3-F4 compensated cirrhosis). Total economic costs were €8548-19 546M. Of these, health system costs were €619-1292M. Total wellbeing costs were €41 536-90 379M. The majority of the undiagnosed population (87.3%-88.2% of total prevalence) was found to have early-stage NASH, which, left untreated, may progress to more resource consuming ESLD over time.

Conclusions: This study found that the majority of economic and wellbeing costs of NASH are experienced in late disease stages. Earlier diagnosis and care of NASH patients could reduce future healthcare costs.
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http://dx.doi.org/10.1111/liv.14825DOI Listing
February 2021

Letter: proton pump inhibitor use and bone fracture risk-a mechanistic point of view. Authors' reply.

Aliment Pharmacol Ther 2021 03;53(5):673

Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

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http://dx.doi.org/10.1111/apt.16257DOI Listing
March 2021

Tumor Incidence in Patients with Non-Alcoholic Fatty Liver Disease.

Dtsch Arztebl Int 2020 Oct;117(43):719-724

Department of Medicine I, University Medical Center MainzMetabolic Liver Diseases, Department of Medicine I, University Medical Center MainzEpidemiology, IQVIA, Frankfurt.

Background: The incidence of cancer is increasing worldwide. The role of comorbidities in this development is debated. The aim of this study was to investigate the significance of non-alcoholic fatty liver disease (NAFLD) for the incidence of cancer of various kinds in Germany.

Methods: Between 2000 and 2015, data on 31 587 patients with established NAFLD were collected for analysis. A control group (n = 31 587) assembled for comparison was matched for sex, age, treating physician, and Charlson Comorbidity Index (CCI).

Results: By 10 years after the index date, 15.3% of patients with NAFLD and 13.4% of patients in the control group had been diagnosed with cancer (p <0.001). Patients with NAFLD exhibited significantly higher rates of male genital cancers (HR 1.26; 95% confidence interval [1.06; 1.5]; p = 0.008), skin cancer (HR 1.22 [1.07; 1.38]; p = 0.002) and breast cancer (HR 1.2 [1.01; 1.43]; p = 0.036). In this analysis, the rate of hepatocellular carcinoma did not differ between patients with NAFLD and patients without NAFLD (0.19% vs. 0.12%; p = 0.204).

Conclusion: NAFLD slightly increases the risk of breast cancer in women, genital cancer in men, and skin cancer irrespective of sex. Thus, NAFLD can be considered a marker of increased cancer risk.
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http://dx.doi.org/10.3238/arztebl.2020.0719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871444PMC
October 2020

Administrative coding in electronic health care record-based research of NAFLD: an expert panel consensus statement.

Hepatology 2021 Jan 23. Epub 2021 Jan 23.

Transplantation and Liver Surgery Clinic, Helsinki University Hospital, Helsinki, Finland.

Background And Aims: Electronic health record (EHR)-based research allows the capture of large amounts of data, which is necessary in nonalcoholic fatty liver disease (NAFLD), where the risk of clinical liver outcomes is generally low. The lack of consensus on which International Classification of Disease (ICD) codes should be used as exposures and outcomes limits comparability and generalizability of results across studies. We aimed to establish consensus among a panel of experts on ICD codes that could become the reference standard and provide guidance around common methodological issues.

Approach And Results: Researchers with an interest in EHR-based NAFLD research were invited to collectively define which administrative codes are most appropriate for documenting exposures and outcomes. We used a modified Delphi approach to reach consensus on several commonly encountered methodological challenges in the field. After two rounds of revision, a high level of agreement (>67%) was reached on all items considered. Full consensus was achieved on a comprehensive list of administrative codes to be considered for inclusion and exclusion criteria in defining exposures and outcomes in EHR-based NAFLD research. We also provide suggestions on how to approach commonly encountered methodological issues and identify areas for future research.

Conclusions: This expert panel consensus statement can help harmonize and improve generalizability of EHR-based NAFLD research.
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http://dx.doi.org/10.1002/hep.31726DOI Listing
January 2021

A randomized placebo-controlled trial of elafibranor in patients with primary biliary cholangitis and incomplete response to UDCA.

J Hepatol 2021 Jan 21. Epub 2021 Jan 21.

Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University Health System, Richmond, Virginia, USA.

Background & Aims: Patients with primary biliary cholangitis (PBC) who have an incomplete response to ursodeoxycholic acid remain at risk of disease progression. We investigated the safety and efficacy of elafibranor, a dual PPARα/δ agonist, in patients with PBC.

Methods: This 12-week, double-blind phase II trial enrolled 45 adults with PBC who had incomplete response to ursodeoxycholic acid (alkaline phosphatase levels ≥1.67-fold the upper limit of normal (ULN). Patients were randomly assigned to elafibranor 80 mg, elafibranor 120 mg or placebo. The primary endpoint was the relative change of ALP at 12 weeks (NCT03124108).

Results: At 12 weeks, ALP was reduced by -48.3±14.8% in the elafibranor 80 mg group (p <0.001 vs. placebo) and by -40.6±17.4% in the elafibranor 120 mg group (p <0.001) compared to a +3.2±14.8% increase in the placebo group. The composite endpoint of ALP ≤1.67-fold the ULN, decrease of ALP >15% and total bilirubin below the ULN was achieved in 67% patients in the elafibranor 80 mg group and 79% patients in the elafibranor 120 mg group, vs. 6.7% patients in the placebo group. Levels of gamma-glutamyltransferase decreased by 37.0±25.5% in the elafibranor 80 mg group (p <0.001) and 40.0±24.1% in the elafibranor 120 mg group (p <0.01) compared to no change (+0.2±26.0%) in the placebo group. Levels of disease markers such as IgM, 5'-nucleotidase or high-sensitivity C-reactive protein were likewise reduced by elafibranor. Pruritus was not induced or exacerbated by elafibranor and patients with pruritus at baseline reported less pruritic symptoms at the end of treatment. All possibly drug-related non-serious adverse events were mild to moderate.

Conclusion: In this randomized phase II trial, elafibranor was generally safe and well tolerated and significantly reduced levels of ALP, composite endpoints of bilirubin and ALP, as well as other markers of disease activity in patients with PBC and an incomplete response to ursodeoxycholic acid.

Lay Summary: Patients with primary biliary cholangitis (a rare chronic liver disease) that do not respond to standard therapy remain at risk of disease progression toward cirrhosis and impaired quality of life. Elafibranor is a nuclear receptor agonist that we tested in a randomized clinical trial over 12 weeks. It successfully decreased levels of disease activity markers, including alkaline phosphatase. Thus, this study is the foundation for a larger prospective study that will determine the efficacy and safety of this drug as a second-line therapy.

Clinical Trial Registration Number: Clinical Trials.gov NCT03124108.
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http://dx.doi.org/10.1016/j.jhep.2021.01.013DOI Listing
January 2021

Multidisciplinary approach to the complex treatment for non-cirrhotic portal hypertension - case-report-based discussion.

Z Gastroenterol 2021 Jan 11;59(1):43-49. Epub 2021 Jan 11.

I. Medizinische Klinik und Poliklinik, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Germany.

Non-cirrhotic portal vein thrombosis (PVT) in patients with antiphospholipid syndrome (APS) is a rare complication, and the management has to be determined individually based on the extent and severity of the presentation. We report on a 37-year-old male patient with non-cirrhotic chronic PVT related to a severe thrombophilia, comprising APS, antithrombin-, factor V- and factor X-deficiency. Three years after the initial diagnosis of non-cirrhotic PVT, the patient presented with severe hemorrhagic shock related to acute bleeding from esophageal varices, requiring an emergency transjugular intrahepatic portosystemic stent shunt (TIPSS). TIPSS was revised after a recurrent bleeding episode due to insufficient reduction of the portal pressure. Additionally, embolization of the dilated V. coronaria ventriculi led to the regression of esophageal varices but resulted simultaneously in a left-sided portal hypertension (LSPH) with development of stomach wall and perisplenic varices. After a third episode of acute esophageal varices bleeding, a surgical distal splenorenal shunt (Warren shunt) was performed to reduce the LSPH. Despite anticoagulation with low molecular weight heparin and antithrombin substitution, endoluminal thrombosis led to a complete Warren shunt occlusion, aggravating the severe splenomegaly and pancytopenia. Finally, a partial spleen embolization (PSE) was performed. In the postinterventional course, leukocyte and platelet counts increased rapidly and the patient showed no further bleeding episodes. Overall, this complex course demonstrates the need for individual assessment of multimodal treatment options in non-cirrhotic portal hypertension. This young patient required triple modality porto-systemic pressure reduction (TIPSS, Warren shunt, PSE) and involved finely balanced anticoagulation and bleeding control.
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http://dx.doi.org/10.1055/a-1330-9827DOI Listing
January 2021

Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis.

Gut 2020 Dec 10. Epub 2020 Dec 10.

Endocrinology and Metabolism, University of Verona Department of Medicine, Verona, Veneto, Italy

Objective: Studies reported a significant association between non-alcoholic fatty liver disease (NAFLD) and increased risk of chronic kidney disease (CKD). However, whether this risk changes with increasing severity of NAFLD remains uncertain. We performed a meta-analysis of observational studies to quantify the magnitude of the association between NAFLD and risk of incident CKD.

Design: We systematically searched PubMed, Web of Science and Scopus from January 2000 to August 2020 using predefined keywords to identify observational studies with a follow-up duration of ≥1 year, in which NAFLD was diagnosed by blood biomarkers/scores, International Classification of Diseases codes, imaging techniques or biopsy. Data from selected studies were extracted, and meta-analysis was performed using random-effects modelling.

Results: 13 studies with 1 222 032 individuals (28.1% with NAFLD) and 33 840 cases of incident CKD stage ≥3 (defined as estimated glomerular filtration rate <60 mL/min/1.73 m, with or without accompanying overt proteinuria) over a median follow-up of 9.7 years were included. NAFLD was associated with a moderately increased risk of incident CKD (n=10 studies; random-effects HR 1.43, 95% CI 1.33 to 1.54; =60.7%). All risks were independent of age, sex, obesity, hypertension, diabetes and other conventional CKD risk factors. Sensitivity analyses did not alter these findings. Funnel plot did not reveal any significant publication bias.

Conclusion: This large and updated meta-analysis indicates that NAFLD is significantly associated with a~1.45-fold increased long-term risk of incident CKD stage ≥3. Further studies are needed to examine the association between the severity of NAFLD and risk of incident CKD.
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http://dx.doi.org/10.1136/gutjnl-2020-323082DOI Listing
December 2020

[Liver-specific diagnostic for non-alcoholic fatty liver disease (NAFLD) - time to replace liver biopsy?]

Z Gastroenterol 2020 Dec 8;58(12):1233-1240. Epub 2020 Dec 8.

Schwerpunkt für Metabolische Lebererkrankungen, I. Medizinische Klinik, Universitätsmedizin Mainz, Mainz, Deutschland.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases. In Germany, the prevalence in the adult population is estimated at 24 % and the incidence is increasing. Prognostically, the distinction between early and advanced stages of the disease is important. In particular, the extent of scarring considered as liver fibrosis is of prognostic significance. Patients with advanced fibrosis and cirrhosis show increased mortality. Liver fibrosis develops as a consequence of a persistent inflammation of the liver tissue over time. Since inflammation and fibrosis are histological features, liver biopsy is considered the reference method in the diagnosis of NAFLD. More recently, non-invasive diagnostic methods for staging (of fibrosis) and grading (activity) of the disease are being developed and validated. The current review summarizes new developments in non-invasive liver diagnostics.
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http://dx.doi.org/10.1055/a-1291-8483DOI Listing
December 2020

Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis.

Sci Transl Med 2020 12;12(572)

Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.

The mechanisms that drive nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This large multicenter study characterized the transcriptional changes that occur in liver tissue across the NAFLD spectrum as disease progresses to cirrhosis to identify potential circulating markers. We performed high-throughput RNA sequencing on a discovery cohort comprising histologically characterized NAFLD samples from 206 patients. Unsupervised clustering stratified NAFLD on the basis of disease activity and fibrosis stage with differences in age, aspartate aminotransferase (AST), type 2 diabetes mellitus, and carriage of , a genetic variant associated with NAFLD. Relative to early disease, we consistently identified 25 differentially expressed genes as fibrosing steatohepatitis progressed through stages F2 to F4. This 25-gene signature was independently validated by logistic modeling in a separate replication cohort ( = 175), and an integrative analysis with publicly available single-cell RNA sequencing data elucidated the likely relative contribution of specific intrahepatic cell populations. Translating these findings to the protein level, SomaScan analysis in more than 300 NAFLD serum samples confirmed that circulating concentrations of proteins AKR1B10 and GDF15 were strongly associated with disease activity and fibrosis stage. Supporting the biological plausibility of these data, in vitro functional studies determined that endoplasmic reticulum stress up-regulated expression of , , and , whereas GDF15 supplementation tempered the inflammatory response in macrophages upon lipid loading and lipopolysaccharide stimulation. This study provides insights into the pathophysiology of progressive fibrosing steatohepatitis, and proof of principle that transcriptomic changes represent potentially tractable and clinically relevant markers of disease progression.
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http://dx.doi.org/10.1126/scitranslmed.aba4448DOI Listing
December 2020

A Sequential Algorithm Combining ADAPT and Liver Stiffness Can Stage Metabolic-Associated Fatty Liver Disease in Hospital-Based and Primary Care Patients.

Am J Gastroenterol 2020 Nov 26. Epub 2020 Nov 26.

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.

Introduction: Metabolic-associated fatty liver disease is common, with fibrosis the major determinant of adverse outcomes. Population-based screening tools with high diagnostic accuracy for the staging of fibrosis are lacking.

Methods: Three independent cohorts, 2 with both liver biopsy and liver stiffness measurements (LSMs, n = 254 and 65) and a population sample (n = 713), were studied. The performance of a recently developed noninvasive algorithm (ADAPT [age, diabetes, PRO-C3 and platelets panel]) as well as aspartate aminotransferase-to-platelet ratio index, fibrosis-4, nonalcoholic fatty liver disease fibrosis score, and LSM was used to stage patients for significant (≥F2) and advanced (≥F3) fibrosis.

Results: In the hospital-based cohorts, the N-terminal propeptide of type 3 collagen (Pro-C3) increased with fibrosis stage (P < 0.0001) and independently associated with advanced fibrosis (odds ratio = 1.091, 95% confidence interval [CI]: 1.053-1.113, P = 0.0001). ADAPT showed areas under the receiver operating characteristics curve of 0.831 (95% CI: 0.779-0.875) in the derivation and 0.879 (95% CI: 0.774-0.946) in the validation cohort for advanced fibrosis. This was superior to the existing fibrosis scores, aspartate aminotransferase-to-platelet ratio index, fibrosis-4, BARD (BMI, aspartate aminotransferase to alanine aminotransferase ratio [AAR], diabetes), and nonalcoholic fatty liver disease fibrosis score in most comparisons and comparable with LSM. Serial use of ADAPT and LSM had diagnostic accuracy of 92.5%, with 98% and 100% negative predictive value in the derivation and validation cohorts, respectively. In the population cohort, PRO-C3 associated with advanced fibrosis (P = 0.04), while ADAPT had a negative predictive value of 98% for excluding advanced fibrosis.

Discussion: PRO-C3 and ADAPT reliably exclude advanced fibrosis in low-risk populations. The serial combination of ADAPT with LSM has high diagnostic accuracy with a low requirement for liver biopsy. The proposed algorithm would help stratify those who need biopsies and narrow down those patients who would need to be referred to specialty clinics.
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http://dx.doi.org/10.14309/ajg.0000000000001059DOI Listing
November 2020

Emerging Pharmacological Treatment in Nonalcoholic Steatohepatitis.

Visc Med 2020 Oct 5;36(5):411-416. Epub 2020 May 5.

Metabolic Liver Research Program, First Department of Medicine, University Medical Center Mainz, Mainz, Germany.

Background: The increasing prevalence of nonalcoholic -fatty liver disease has led to a strong demand for an optimal therapeutic approach. At present, guidelines recommend lifestyle changes, but it has become apparent that pharmacotherapy will be required in patients with advanced disease to prevent the progression to end-stage liver disease and potentially improve extrahepatic outcomes.

Summary: This review discusses current pharmacological approaches focusing on substances studied in pivotal trials and selected phase 2 trials in patients with nonalcoholic steatohepatitis (NASH) and fibrosis.

Key Message: Currently, several compounds are subjected to clinical testing to explore predominantly anti-inflammatory, anti-fibrotic, and metabolic treatment for NASH. With current response rates around 20%, the combination of several drugs targeting more than one pathway could lead to increased treatment success in the future.
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http://dx.doi.org/10.1159/000507231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672521PMC
October 2020

The nonalcoholic steatohepatitis (NASH) drug development graveyard: established hurdles and planning for future success.

Expert Opin Investig Drugs 2020 Dec 27;29(12):1365-1375. Epub 2020 Oct 27.

Department of Medicine, University Medical Centre of the Johannes Gutenberg-University , Mainz, Germany.

Introduction: Numerous pharmacological compounds that target the different molecular targets involved in the pathobiology of nonalcoholic steatohepatitis (NASH) are currently in clinical testing. So far, there are no regulatory approvals.

Areas Covered: This paper sheds light on the molecular pathways involved in NASH and the drugs targeting these pathways. We have identified 10 compounds whose clinical development program has been halted. Moreover, we explore early phase clinical trials and dissect the reasons for termination of development.

Expert Opinion: The main goal of NASH pharmacotherapy is to halt or reverse hepatic fibrosis or to achieve the resolution of steatohepatitis. There is an intense competition to develop compounds with disease-modulating properties with a focus on anti-metabolic, anti-inflammatory or anti-fibrotic properties. Numerous study programs, even in late-phase trials, have been halted because of lack of efficacy, safety concerns or drug-drug interactions. This underscores the urgent need to provide robust preclinical data and an extensive clinical trial program that builds on reliable data generated in earlier stages of clinical development before moving into late stage development.
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http://dx.doi.org/10.1080/13543784.2020.1839888DOI Listing
December 2020

The European NAFLD Registry: A real-world longitudinal cohort study of nonalcoholic fatty liver disease.

Contemp Clin Trials 2020 Nov 9;98:106175. Epub 2020 Oct 9.

Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom. Electronic address:

Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma. At present our understanding of pathogenesis, disease natural history and long-term outcomes remain incomplete. There is a need for large, well characterised patient cohorts that may be used to address these knowledge gaps and to support the development of better biomarkers and novel therapies. The European NAFLD Registry is an international, prospectively recruited observational cohort study that aims to establish a large, highly-phenotyped patient cohort and linked bioresource. Here we describe the infrastructure, data management and monitoring plans, and the standard operating procedures implemented to ensure the timely and systematic collection of high-quality data and samples. Already recruiting subjects at secondary/tertiary care centres across Europe, the Registry is supporting the European Union IMI2-funded LITMUS 'Liver Investigation: Testing Marker Utility in Steatohepatitis' consortium, which is a major international effort to robustly validate biomarkers that diagnose, risk stratify and/or monitor NAFLD progression and liver fibrosis stage. The European NAFLD Registry has the demonstrable capacity to support research and biomarker development at scale and pace.
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http://dx.doi.org/10.1016/j.cct.2020.106175DOI Listing
November 2020

Incident Dementia in Elderly Patients with Nonalcoholic Fatty Liver Disease in Germany.

Dig Dis Sci 2020 Oct 10. Epub 2020 Oct 10.

Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

Dementia and NAFLD are two frequent conditions that share underlying risk factors mainly in the realm of metabolic disease. Additionally, an association between NAFLD and brain aging has been proposed. Therefore, we investigated the hypothesis if NAFLD is an independent risk factor for emerging dementia. In this population-based cohort study, elderly patients (≥ 65 years) with NAFLD diagnosed between 2000 and 2015 were matched 1:1 to a cohort without NAFLD based on ICD-10 coding in the Disease Analyzer database. Matching criteria were age, sex, physician, index year, and co-diagnoses associated with dementia. The primary outcomes of this study were all-cause dementia diagnoses, the incidence of vascular dementia, and antidementive drug prescription. A total of 22,317 patients with NAFLD were matched to 22,317 patients without NAFLD. Within 10 years of the index date, 16.0% of patients with NAFLD and 15.6% of the patients without NAFLD were diagnosed with dementia. On Cox regression analysis, there is no association between NAFLD and the incidence of all-cause dementia (HR 0.97, 95% CI 0.92-1.04), vascular dementia (HR 0.89, 95% CI 0.78-1.02), or the new prescription of antidementive therapy (HR 0.87, 95% CI 0.76-1.01). In sensitivity analyses, there was no association between NAFLD and dementia in different age-groups as well as men or women. In conclusion, in this database study of elderly patients coded with NAFLD no independent association with incident dementia was detected. Risk assessment regarding dementia in patients with NAFLD should be carried out in the same way as for metabolic burdened patients.
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http://dx.doi.org/10.1007/s10620-020-06644-1DOI Listing
October 2020

The Fatty Liver Assessment in Germany (FLAG) cohort study identifies large heterogeneity in NAFLD care.

JHEP Rep 2020 Dec 4;2(6):100168. Epub 2020 Aug 4.

I. Department of Medicine, University Medical Centre of the Johannes Gutenberg-University, Mainz, Germany.

Background & Aims: NAFLD is a growing health concern. The aim of the Fatty Liver Assessment in Germany (FLAG) study was to assess disease burden and provide data on the standard of care from secondary care.

Methods: The FLAG study is an observational real-world study in patients with NAFLD enrolled at 13 centres across Germany. Severity of disease was assessed by non-invasive surrogate scores and data recorded at baseline and 12 months.

Results: In this study, 507 patients (mean age 53 years; 47% women) were enrolled. According to fibrosis-4 index, 64%, 26%, and 10% of the patients had no significant fibrosis, indeterminate stage, and advanced fibrosis, respectively. Patients with advanced fibrosis were older, had higher waist circumferences, and higher aspartate aminotransferase and gamma-glutamyltransferase as well as ferritin levels. The prevalence of obesity, arterial hypertension, and type 2 diabetes increased with fibrosis stages. Standard of care included physical exercise >2 times per week in 17% (no significant fibrosis), 19% (indeterminate), and 6% (advanced fibrosis) of patients. Medication with either vitamin E, silymarin, or ursodeoxycholic acid was reported in 5%. Approximately 25% of the patients received nutritional counselling. According to the FibroScan-AST score, 17% of patients presented with progressive non-alcoholic steatohepatitis (n = 107). On follow-up at year 1 (n = 117), weight loss occurred in 47% of patients, of whom 17% lost more than 5% of body weight. In the weight loss group, alanine aminotransferase activities were reduced by 20%.

Conclusions: This is the first report on NAFLD from a secondary-care real-world cohort in Germany. Every 10th patient presented with advanced fibrosis at baseline. Management consisted of best supportive care and lifestyle recommendations. The data highlight the urgent need for systematic health agenda in NAFLD patients.

Lay Summary: FLAG is a real-world cohort study that examined the liver disease burden in secondary and tertiary care. Herein, 10% of patients referred to secondary care for NAFLD exhibited advanced liver disease, whilst 64% had no significant liver scarring. These findings underline the urgent need to define patient referral pathways for suspected liver disease.
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http://dx.doi.org/10.1016/j.jhepr.2020.100168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490844PMC
December 2020

On the value and limitations of liver histology in assessing non-alcoholic steatohepatitis.

J Hepatol 2020 12 12;73(6):1592-1593. Epub 2020 Sep 12.

Institute of Pathology, University Medical Center Mainz, Johannes Gutenberg-University Mainz.

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http://dx.doi.org/10.1016/j.jhep.2020.07.020DOI Listing
December 2020

Nonalcoholic Fatty Liver Disease Increases the Risk of Anxiety and Depression.

Hepatol Commun 2020 Sep 22;4(9):1293-1301. Epub 2020 Jun 22.

I. Department of Medicine University Medical Center of the Johannes Gutenberg University Mainz Germany.

Nonalcoholic fatty liver disease (NAFLD), depression, and anxiety disorders are frequent diseases, and data on mutual influence are inconsistent. The aim of this study was to explore the incidence of depression and anxiety in a large primary care cohort in Germany and to study the impact of NAFLD over a 10-year time frame. Patients with NAFLD diagnosed between 2010 and 2015 were matched to a cohort without NAFLD controlling for age, sex, physician, index year, and Charlson comorbidity index. The primary outcome of the study was the incidence of depression, anxiety, and first prescription of antidepressant drugs. We compared 19,871 patients with NAFLD to 19,871 matched controls. Within 10 years of the index date, 21.2% of patients with NAFLD and 18.2% of controls were diagnosed with depression ( < 0.001). On regression analysis, the hazard ratio (HR) for incidence of depression was 1.21 ( < 0.001). This association was similar for the endpoint of the first prescription of antidepressant drugs (HR, 1.21;  < 0.001). Anxiety disorders were diagnosed in 7.9% of patients with NAFLD and 6.5% of controls during the observation time ( = 0.003). The HR for incidence of anxiety was 1.23 ( < 0.001). This association remained significant in women ( < 0.001), while there was only a trend in men (HR, 1.15; 95% confidence interval, 0.99-1.34;  < 0.067). The risk of developing anxiety disorders was higher in younger patients. NAFLD constitutes an independent risk factor for emerging depression and anxiety even after controlling for confounding comorbidities.
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http://dx.doi.org/10.1002/hep4.1541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471420PMC
September 2020

Impact of non-selective ß-blockers on hepatic encephalopathy in patients with liver cirrhosis.

Eur J Intern Med 2020 12 29;82:83-89. Epub 2020 Aug 29.

Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany; Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. Electronic address:

Background: Non-selective β-blockers (NSBB) are frequently used for the treatment of portal hypertension and gastroesophageal varices in patients with liver cirrhosis; however prospective studies investigating the potential association between NSBB use and hepatic encephalopathy (HE) are still scarce. We investigated the potential association between NSBB use and the presence of covert HE (CHE) as well as the development of overt HE (OHE).

Methods: 224 patients with liver cirrhosis were included into this cohort study at two German centers and followed for a median of 364 days. CHE was diagnosed by pathological results in the PHES. Predictors for the presence of CHE or the development of OHE were analyzed using logistic-regression or cox-regression models.

Results: 39% of patients were treated with NSBB and CHE was detected in 34% of patients at study inclusion. In logistic regression analysis, NSBB use, higher MELD score and a history of OHE were independently associated with the presence of CHE. Cumulative incidence of OHE was considerably higher in NSBB users than in non-users (p<0.001). In Cox-regression models NSBB use, presence of CHE, lower albumin and higher MELD score were independently associated with the development of OHE in the whole cohort as well as in the subgroup of patients with decompensated liver cirrhosis. NSBB use was independently associated with higher risk of mortality or need for liver transplantation in decompensated patients but not in the total cohort.

Conclusion: NSBB use seems to be associated with the presence of CHE as well as the development of OHE in patients with decompensated liver cirrhosis.
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http://dx.doi.org/10.1016/j.ejim.2020.08.022DOI Listing
December 2020

Long-term outcome in PSC patients receiving azathioprine: Does immunosuppression have a positive effect on survival?

J Hepatol 2020 11 27;73(5):1285-1287. Epub 2020 Aug 27.

I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany; European Reference Network - Hepatological Diseases (ERN RARE-LIVER).

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http://dx.doi.org/10.1016/j.jhep.2020.07.027DOI Listing
November 2020

Intestinal motility: a therapeutic target for NAFLD?

Lancet Gastroenterol Hepatol 2020 11 15;5(11):957-958. Epub 2020 Aug 15.

Metabolic Liver Research Program, Department of Internal Medicine, University Medical Center Mainz, 55131 Mainz, Germany. Electronic address:

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http://dx.doi.org/10.1016/S2468-1253(20)30204-1DOI Listing
November 2020

Liver injury in patients with severe acute respiratory syndrome coronavirus-2 infection: a systematic review and meta-analysis.

Eur J Gastroenterol Hepatol 2020 Aug 10. Epub 2020 Aug 10.

Department of Internal Medicine I.

Objective: Coronavirus disease-19 (COVID-19) infection is a global health threat. To inform the liver community on the potential relevance of COVID-19, we performed a systematic review and meta-analysis of published data on liver injury in patients with COVID-19 infection.

Methods: We searched PubMed and Google Scholar through 22 March according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled data were analyzed by using random-effects meta-analyses.

Results: A total of 14 studies combining data from 2.871 patients were identified. The prevalence of pre-existing liver disease was reported at 3.1%. The pooled prevalence of elevated aspartate aminotransferase (AST) and alanine transaminase (ALT) levels were 26% [95% confidence interval (CI), 20-32%] and 19% (95% CI, 14-26%), respectively. Only two studies reported the prevalence of elevated liver function tests according to normal ward versus ICU and here the frequency of elevated levels of AST was 50% and 62% versus ALT 40.8% and thus quantitatively higher in ICU-treated patients. Mean levels of absolute AST levels were 33 U/L (95% CI, 30.21-36.09), while mean ALT levels were 31 U/L (95% CI, 27.52-34.57). Cholestatic liver function tests were only incompletely reported in 510 patients. Here, mean levels of alkaline phosphatase were 71 U/L across three studies, and mean levels of gamma-glutamyl transferase were 40.6 U/L across four studies.

Conclusions: Emerging data on LFTs in COVID-19 are heterogeneous indicating mild LFTs involvement in every fourth to fifth patients with numerical more prevalent AST over ALT elevations. Prospective studies are needed to define the clinical relevance of liver injury in COVID-19.
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http://dx.doi.org/10.1097/MEG.0000000000001827DOI Listing
August 2020

Response: Frailty assessment in the COVID-19 pandemic.

J Investig Med 2020 10 13;68(7):1302. Epub 2020 Aug 13.

Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

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http://dx.doi.org/10.1136/jim-2020-001556DOI Listing
October 2020

Cost of non-alcoholic steatohepatitis in Europe and the USA: The GAIN study.

JHEP Rep 2020 Oct 15;2(5):100142. Epub 2020 Jul 15.

Institute of Translational and Clinical Research, Faculty of Medical Sciences, Newcastle University, Newcastle-upon-Tyne, UK.

Background & Aims: Non-alcoholic steatohepatitis (NASH) leads to cirrhosis and is associated with a substantial socioeconomic burden, which, coupled with rising prevalence, is a growing public health challenge. However, there are few real-world data available describing the impact of NASH.

Methods: The Global Assessment of the Impact of NASH (GAIN) study is a prevalence-based burden of illness study across Europe (France, Germany, Italy, Spain, and the UK) and the USA. Physicians provided demographic, clinical, and economic patient information via an online survey. In total, 3,754 patients found to have NASH on liver biopsy were stratified by fibrosis score and by biomarkers as either early or advanced fibrosis. Per-patient costs were estimated using national unit price data and extrapolated to the population level to calculate the economic burden. Of the patients, 767 (20%) provided information on indirect costs and health-related quality of life using the EuroQOL 5-D (EQ-5D; n = 749) and Chronic Liver Disease Questionnaire - Non-Alcoholic Fatty Liver Disease (CLDQ-NAFLD) (n = 723).

Results: Mean EQ-5D and CLDQ-NAFLD index scores were 0.75 and 4.9, respectively. For 2018, the mean total annual per patient cost of NASH was €2,763, €4,917, and €5,509 for direct medical, direct non-medical, and indirect costs, respectively. National per-patient cost was highest in the USA and lowest in France. Costs increased with fibrosis and decompensation, driven by hospitalisation and comorbidities. Indirect costs were driven by work loss.

Conclusions: The GAIN study provides real-world data on the direct medical, direct non-medical, and indirect costs associated with NASH, including patient-reported outcomes in Europe and the USA, showing a substantial burden on health services and individuals.

Lay Summary: There has been little research into the socioeconomic burden associated with non-alcoholic steatohepatitis (NASH). The GAIN study provides real-world data on the direct medical, direct non-medical, and indirect costs associated with NASH, including patient-reported outcomes in five European countries (UK, France, Germany, Spain, and Italy) and the USA. Mean total annual per patient cost of NASH was estimated at €2,763, €4,917, and €5,509 for the direct medical, direct non-medical, and indirect cost categories, respectively.
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http://dx.doi.org/10.1016/j.jhepr.2020.100142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397699PMC
October 2020

NAFLD between genes and environment: what drives fibrogenesis?

Gut 2021 May 5;70(5):815-816. Epub 2020 Aug 5.

Department of Medicine, University Medical Center Mainz Department of Internal Medicine 1, Mainz, Rheinland-Pfalz, Germany

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http://dx.doi.org/10.1136/gutjnl-2020-321964DOI Listing
May 2021

Proton pump inhibitors increase risk of bone fractures in men with cirrhosis: a population-based study.

Aliment Pharmacol Ther 2020 09 30;52(6):1042-1050. Epub 2020 Jul 30.

Epidemiology, IQVIA, Frankfurt am Main, Germany.

Background: Bone fractures are a frequent complication in patients with cirrhosis. Proton pump inhibitors (PPIs) are among the most frequently prescribed medications and may impair bone quality and quantity.

Aims: To investigate whether PPI use predisposes patients with cirrhosis to bone fractures.

Methods: We performed a population-based case-control study exploring a sample of patients with cirrhosis derived from the Disease Analyzer database. In total, 1795 cirrhotic patients with fractures were compared to 10 235 cirrhotic patients without fractures. PPI use overall and the cumulative PPI dose 5 years prior to the index date were analysed. To estimate the association between PPI use and fractures, logistic regression analyses were performed taking cofounding factors into consideration.

Results: PPI use was more frequently seen in cirrhotic patients with fractures compared to controls (67.0% vs 53.4%, P < 0.001). In regression analyses, PPI use was associated with bone fractures after adjusting for important confounders (OR 1.34, 95% CI 1.20-1.51, P < 0.001). Importantly, the strongest effect of PPIs on bone fractures was seen in men and patients below 70 years of age. On further sensitivity analyses, we observed a dose-dependent effect for all PPIs with the strongest effect in cirrhotic patients receiving a dose of >50 000 mg during the 5 years prior to index date (OR 1.63, 95% CI 1.32-2.03).

Conclusions: PPI use was associated with bone fractures in a dose-dependent fashion in patients with cirrhosis. PPI use in these patients should be based on a careful risk-benefit assessment.
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http://dx.doi.org/10.1111/apt.16008DOI Listing
September 2020