Publications by authors named "Frank Tacke"

498 Publications

Molecular and Cellular Mediators of the Gut-Liver Axis in the Progression of Liver Diseases.

Front Med (Lausanne) 2021 28;8:725390. Epub 2021 Sep 28.

Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany.

The gut-liver axis covers the bidirectional communication between the gut and the liver, and thus includes signals from liver-to-gut (e.g., bile acids, immunoglobulins) and from gut-to-liver (e.g., nutrients, microbiota-derived products, and recirculating bile acids). In a healthy individual, liver homeostasis is tightly controlled by the mostly tolerogenic liver resident macrophages, the Kupffer cells, capturing the gut-derived antigens from the blood circulation. However, disturbances of the gut-liver axis have been associated to the progression of varying chronic liver diseases, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and primary sclerosing cholangitis. Notably, changes of the gut microbiome, or intestinal dysbiosis, combined with increased intestinal permeability, leads to the translocation of gut-derived bacteria or their metabolites into the portal vein. In the context of concomitant or subsequent liver inflammation, the liver is then infiltrated by responsive immune cells (e.g., monocytes, neutrophils, lymphoid, or dendritic cells), and microbiota-derived products may provoke or exacerbate innate immune responses, hence perpetuating liver inflammation and fibrosis, and potentiating the risks of developing cirrhosis. Similarly, food derived antigens, bile acids, danger-, and pathogen-associated molecular patterns are able to reshape the liver immune microenvironment. Immune cell intracellular signaling components, such as inflammasome activation, toll-like receptor or nucleotide-binding oligomerization domain-like receptors signaling, are potent targets of interest for the modulation of the immune response. This review describes the current understanding of the cellular landscape and molecular pathways involved in the gut-liver axis and implicated in chronic liver disease progression. We also provide an overview of innovative therapeutic approaches and current clinical trials aiming at targeting the gut-liver axis for the treatment of patients with chronic liver and/or intestinal diseases.
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http://dx.doi.org/10.3389/fmed.2021.725390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505679PMC
September 2021

[Management of acutely decompensated liver cirrhosis in emergency and critical care medicine].

Med Klin Intensivmed Notfmed 2021 Oct 12. Epub 2021 Oct 12.

Klinik für Akut- und Notfallmedizin, St.-Antonius-Hospital Eschweiler, Eschweiler, Deutschland.

Acute decompensation in patients with liver cirrhosis is characterized by the development of ascites, gastrointestinal bleeding, hepatic encephalopathy, or bacterial infection and is often accompanied by further extrahepatic organ dysfunction. Since critically ill patients with decompensated cirrhosis have a high mortality risk, rapid identification and treatment of the triggering event of decompensation (e.g., infection, hemorrhage, drugs) as well as specific measures for the treatment of concomitant extrahepatic organ dysfunctions are essential in order to improve the patient's prognosis and to prevent the development of acute-on-chronic liver failure (ACLF).
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http://dx.doi.org/10.1007/s00063-021-00876-3DOI Listing
October 2021

Evolution of Nonmalignant Portal Vein Thrombosis in Liver Cirrhosis: A Pictorial Review.

Clin Transl Gastroenterol 2021 Oct 1;12(10):e00409. Epub 2021 Oct 1.

Liver Cirrhosis Study Group, Department of Gastroenterology, The General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, China.

Portal vein thrombosis (PVT) is a common complication in liver cirrhosis, especially in advanced cirrhosis. It may be related to a higher risk of liver-related events and liver function deterioration. Imaging examinations can not only provide an accurate diagnosis of PVT, such as the extent of thrombus involvement and the degree of lumen occupied, but also identify the nature of thrombus (i.e., benign/malignant and acute/chronic). Evolution of PVT, mainly including development, recanalization, progression, stability, and recurrence, could also be assessed based on the imaging examinations. This article briefly reviews the pathophysiology, diagnosis, classification, and evolution of PVT with an emphasis on their computed tomography imaging features.
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http://dx.doi.org/10.14309/ctg.0000000000000409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483868PMC
October 2021

Serum Perilipin 2 (PLIN2) Predicts Multiple Organ Dysfunction in Critically Ill Patients.

Biomedicines 2021 Sep 13;9(9). Epub 2021 Sep 13.

Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany.

Perilipin 2 (PLIN2) is a lipid droplet protein with various metabolic functions. However, studies investigating PLIN2 in the context of inflammation, especially in systemic and acute inflammation, are lacking. Hence, we assessed the relevance of serum PLIN2 in critically ill patients. We measured serum PLIN2 serum in 259 critically ill patients (166 with sepsis) upon admission to a medical intensive care unit (ICU) compared to 12 healthy controls. A subset of 36 patients underwent computed tomography to quantify body composition. Compared to controls, serum PLIN2 concentrations were elevated in critically ill patients at ICU admission. Interestingly, PLIN2 independently indicated multiple organ dysfunction (MOD), defined as a SOFA score > 9 points, at ICU admission, and was also able to independently predict MOD after 48 h. Moreover, serum PLIN2 levels were associated with severe respiratory failure potentially reflecting a moribund state. However, PLIN2 was neither a predictor of ICU mortality nor did it reflect metabolic dysregulation. Conclusively, the first study assessing serum PLIN2 in critical illness proved that it may assist in risk stratification because it is capable of independently indicating MOD at admission and predicting MOD 48 h after PLIN2 measurement. Further evaluation regarding the underlying mechanisms is warranted.
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http://dx.doi.org/10.3390/biomedicines9091210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468514PMC
September 2021

Safety of transanal ileal pouch-anal anastomosis for ulcerative colitis: a retrospective observational cohort study.

Patient Saf Surg 2021 Sep 18;15(1):31. Epub 2021 Sep 18.

Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.

Background: Colectomy with transanal ileal pouch-anal anastomosis (taIPAA) is a surgical technique that can be used to treat benign colorectal disease. Ulcerative colitis is the most frequent inflammatory bowel disease (IBD) and although pharmacological therapy has improved, colectomy rates reach up to 15%. The objective of this study was to determine anastomotic leakage rates and treatment after taIPAA as well as short- and long-term pouch function.

Methods: We conducted a retrospective analysis of a prospective database of all patients undergoing taIPAA at an academic tertiary referral center in Germany, between 01/03/2015 and 31/08/2019. Patients with indications other than ulcerative colitis or with adjuvant chemotherapy following colectomy for colorectal carcinoma were excluded for short- and long-term follow up due to diverging postoperative care yet considered for evaluation of anastomotic leakage.

Results: A total of 22 patients undergoing taIPAA during the study time-window were included in analysis. Median age at the time of surgery was 32 ± 12.5 (14-54) years. Two patients developed an anastomotic leakage at 11 days (early anastomotic leakage) and 9 months (late anastomotic leakage) after surgery, respectively. In both patients, pouches could be preserved with a multimodal approach. Twenty patients out of 22 met the inclusion criteria for short and long term follow-up. Data on short-term pouch function could be obtained in 14 patients and showed satisfactory pouch function with only four patients reporting intermittent incontinence at a median stool frequency of 9-10 times per day. In the long-term we observed an inflammation or "pouchitis" in 11 patients and a pouch failure in one patient.

Conclusion: Postoperative complication rates in patients with benign colorectal disease remain an area of concern for surgical patient safety. In this pilot study on 22 selected patients, taIPAA was associated with two patients developing anastomotic leakage. Future large-scale validation studies are required to determine the safety and feasibility of taIPAA in patients with ulcerative colitis.
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http://dx.doi.org/10.1186/s13037-021-00306-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449900PMC
September 2021

An elevated FIB-4 score predicts liver cancer development: a longitudinal analysis from 29,999 NAFLD patients: Reply to: "EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis- 2021 update".

J Hepatol 2021 Sep 11. Epub 2021 Sep 11.

Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2021.08.030DOI Listing
September 2021

Elevated Flt3L Predicts Long-Term Survival in Patients with High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms.

Cancers (Basel) 2021 Sep 4;13(17). Epub 2021 Sep 4.

Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.

Background: The clinical management of high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is challenging due to disease heterogeneity, illustrating the need for reliable biomarkers facilitating patient stratification and guiding treatment decisions. FMS-like tyrosine kinase 3 ligand (Flt3L) is emerging as a prognostic or predictive surrogate marker of host tumoral immune response and might enable the stratification of patients with otherwise comparable tumor features.

Methods: We evaluated Flt3L gene expression in tumor tissue as well as circulating Flt3L levels as potential biomarkers in a cohort of 54 patients with GEP-NEN.

Results: We detected a prominent induction of Flt3L gene expression in individual G2 and G3 NEN, but not in G1 neuroendocrine tumors (NET). Flt3L mRNA expression levels in tumor tissue predicted the disease-related survival of patients with highly proliferative G2 and G3 NEN more accurately than the conventional criteria of grading or NEC/NET differentiation. High level Flt3L mRNA expression was associated with the increased expression of genes related to immunogenic cell death, lymphocyte effector function and dendritic cell maturation, suggesting a less tolerogenic (more proinflammatory) phenotype of tumors with Flt3L induction. Importantly, circulating levels of Flt3L were also elevated in high grade NEN and correlated with patients' progression-free and disease-related survival, thereby reflecting the results observed in tumor tissue.

Conclusions: We propose Flt3L as a prognostic biomarker for high grade GEP-NEN, harnessing its potential as a marker of an inflammatory tumor microenvironment. Flt3L measurements in serum, which can be easily be incorporated into clinical routine, should be further evaluated to guide patient stratification and treatment decisions.
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http://dx.doi.org/10.3390/cancers13174463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430927PMC
September 2021

Circulating Osteopontin Levels and Outcomes in Patients Hospitalized for COVID-19.

J Clin Med 2021 Aug 30;10(17). Epub 2021 Aug 30.

Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital Düsseldorf, 40225 Düsseldorf, Germany.

Background: Severe coronavirus disease 2019 (COVID-19) is the result of a hyper-inflammatory reaction to the severe acute respiratory syndrome coronavirus 2. The biomarkers of inflammation have been used to risk-stratify patients with COVID-19. Osteopontin (OPN) is an integrin-binding glyco-phosphoprotein involved in the modulation of leukocyte activation; its levels are associated with worse outcomes in patients with sepsis. Whether OPN levels predict outcomes in COVID-19 is unknown.

Methods: We measured OPN levels in serum of 341 hospitalized COVID-19 patients collected within 48 h from admission. We characterized the determinants of OPN levels and examined their association with in-hospital outcomes; notably death, need for mechanical ventilation, and need for renal replacement therapy (RRT) and as a composite outcome. The risk discrimination ability of OPN was compared with other inflammatory biomarkers.

Results: Patients with COVID-19 (mean age 60, 61.9% male, 27.0% blacks) had significantly higher levels of serum OPN compared to healthy volunteers (96.63 vs. 16.56 ng/mL, < 0.001). Overall, 104 patients required mechanical ventilation, 35 needed dialysis, and 53 died during their hospitalization. In multivariable analyses, OPN levels ≥140.66 ng/mL (third tertile) were associated with a 3.5 × (95%CI 1.44-8.27) increase in the odds of death, and 4.9 × (95%CI 2.48-9.80) increase in the odds of requiring mechanical ventilation. There was no association between OPN and need for RRT. Finally, OPN levels in the upper tertile turned out as an independent prognostic factor of event-free survival with respect to the composite endpoint.

Conclusion: Higher OPN levels are associated with increased odds of death and mechanical ventilation in patients with COVID-19, however, their utility in triage is questionable.
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http://dx.doi.org/10.3390/jcm10173907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432103PMC
August 2021

Telomere Shortening in Peripheral Leukocytes Is Associated With Poor Survival in Cancer Patients Treated With Immune Checkpoint Inhibitor Therapy.

Front Oncol 2021 19;11:729207. Epub 2021 Aug 19.

Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Background: Immune checkpoint inhibitor (ICI) therapy represents a new standard of care for an increasing number of malignancies. Nevertheless, response rates and outcome of ICI treatment vary between individuals and the identification of predictive markers or hints towards immune cell exhaustion during therapy has remained a major challenge. Leukocyte telomere length is an established predictive biomarker of replicative aging and cellular proliferative potential in various hematological diseases. However, its relevance in the context of ICI therapy has not been investigated to date. Here, we analyze the age-adapted delta telomere length (ΔTL) of peripheral leukocytes as a potential predictive and prognostic marker in patients undergoing ICI therapy.

Methods: Age-adapted delta telomere length (ΔTL) of 84 patients treated with ICIs for solid malignancies was measured quantitative real-time PCR. ΔTL was correlated with outcome and clinical data.

Results: ΔTL was not significantly altered between patients with different tumor entities or tumor stages and did not predict tumor response to ICI therapy. However, ΔTLs at initiation of treatment were a prognostic marker for overall survival (OS). When using a calculated ideal cut-off value, the median OS in patients with shorter ΔTL was 5.7 months compared to 18.0 months in patients showing longer ΔTL. The prognostic role of age-adapted ΔTL was further confirmed by uni- and multivariate Cox-regression analyses.

Conclusion: In the present study, we demonstrate that shorter telomere lengths in peripheral blood leukocytes are associated with a significantly impaired outcome in patients receiving ICI therapy across different malignancies. We explain our findings by hypothesizing an older replicative age in peripheral leukocytes of patients with an impaired overall survival, reflected by a premature TL shortening. Whether this association is ICI-specific remains unknown. Further follow-up studies are needed to provide insights about the exact mechanism of how shortened telomeres eventually affect OS and could help guiding therapeutic decisions in future.
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http://dx.doi.org/10.3389/fonc.2021.729207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417059PMC
August 2021

The Role of miRNA in the Pathophysiology of Neuroendocrine Tumors.

Int J Mol Sci 2021 Aug 9;22(16). Epub 2021 Aug 9.

Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.

Neuroendocrine tumors (NETs) represent a tumor group that is both rare and heterogeneous. Prognosis is largely determined by the tumor grading and the site of the primary tumor and metastases. Despite intensive research efforts, only modest advances in diagnostic and therapeutic approaches have been achieved in recent years. For patients with non-respectable tumor stages, prognosis is poor. In this context, the development of novel diagnostic tools for early detection of NETs and prediction of tumor response to therapy as well as estimation of the overall prognosis would greatly improve the clinical management of NETs. However, identification of novel diagnostic molecules is hampered by an inadequate understanding of the pathophysiology of neuroendocrine malignancies. It has recently been demonstrated that microRNA (miRNA), a family of small RNA molecules with an established role in the pathophysiology of quite different cancer entities, may also play a role as a biomarker. Here, we summarize the available knowledge on the role of miRNAs in the development of NET and highlight their potential use as serum-based biomarkers in the context of this disease. We discuss important challenges currently preventing their use in clinical routine and give an outlook on future directions of miRNA research in NET.
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http://dx.doi.org/10.3390/ijms22168569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395312PMC
August 2021

Decreased Bone Mineral Density Is a Predictor of Poor Survival in Critically Ill Patients.

J Clin Med 2021 Aug 23;10(16). Epub 2021 Aug 23.

Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany.

Alterations in bone mineral density (BMD) have been suggested as independent predictors of survival for several diseases. However, little is known about the role of BMD in the context of critical illness and intensive care medicine. We therefore evaluated the prognostic role of BMD in critically ill patients upon admission to an intensive care unit (ICU). Routine computed tomography (CT) scans of 153 patients were used to assess BMD in the first lumbar vertebra. Results were correlated with clinical data and outcomes. While median BMD was comparable between patients with and without sepsis, BMD was lower in patients with pre-existing arterial hypertension or chronic obstructive pulmonary disease. A low BMD upon ICU admission was significantly associated with impaired short-term ICU survival. Moreover, patients with baseline BMD < 122 HU had significantly impaired overall survival. The prognostic relevance of low BMD was confirmed in uni- and multivariate Cox-regression analyses including several clinicopathological parameters. In the present study, we describe a previously unrecognised association of individual BMD with short- and long-term outcomes in critically ill patients. Due to its easy accessibility in routine CT, BMD provides a novel prognostic tool to guide decision making in critically ill patients.
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http://dx.doi.org/10.3390/jcm10163741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397072PMC
August 2021

Cardiac Magnetic Resonance Reveals Incipient Cardiomyopathy Traits in Adult Patients With Phenylketonuria.

J Am Heart Assoc 2021 Sep 21;10(17):e020351. Epub 2021 Aug 21.

Department of Cardiology German Heart Centre Berlin Berlin Germany.

Background Phenylketonuria is the most common inborn error of amino acid metabolism, where oxidative stress and collateral metabolic abnormalities are likely to cause cardiac structural and functional modifications. We aim herein to characterize the cardiac phenotype of adult subjects with phenylketonuria using advanced cardiac imaging. Methods and Results Thirty-nine adult patients with phenylketonuria (age, 30.5±8.7 years; 10-year mean phenylalanine concentration, 924±330 µmol/L) and 39 age- and sex-matched healthy controls were investigated. Participants underwent a comprehensive cardiac magnetic resonance and echocardiography examination. Ten-year mean plasma levels of phenylalanine and tyrosine were used to quantify disease activity and adherence to treatment. Patients with phenylketonuria had thinner left ventricular walls (septal end-diastolic thickness, 7.0±17 versus 8.8±1.7 mm [<0.001]; lateral thickness, 6.1±1.4 versus 6.8±1.2 mm [=0.004]), more dilated left ventricular cavity (end-diastolic volume, 87±14 versus 80±14 mL/m [=0.0178]; end-systolic volume, 36±9 versus 29±8 mL/m [<0.001]), lower ejection fraction (59±6% versus 64±6% [<0.001]), reduced systolic deformation (global circumferential strain, -29.9±4.2 % versus -32.2±5.0 % [=0.027]), and lower left ventricular mass (38.2±7.9 versus 47.8±11.0 g/m [<0.001]). T1 native values were decreased (936±53 versus 996±26 ms [<0.001]), with particular low values in patients with phenylalanine >1200 µmol/L (909±48 ms). Both mean phenylalanine (=0.013) and tyrosine (=0.035) levels were independently correlated with T1; and in a multiple regression model, higher phenylalanine levels and higher left ventricular mass associate with lower T1. Conclusions Cardiac phenotype of adult patients with phenylketonuria reveals some traits of an early-stage cardiomyopathy. Regular cardiology follow-up, tighter therapeutic control, and prophylaxis of cardiovascular risk factors, in particular dyslipidemia, are recommended.
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http://dx.doi.org/10.1161/JAHA.120.020351DOI Listing
September 2021

The APAC Score: A Novel and Highly Performant Serological Tool for Early Diagnosis of Hepatocellular Carcinoma in Patients with Liver Cirrhosis.

J Clin Med 2021 Jul 30;10(15). Epub 2021 Jul 30.

Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Augustenburger Platz 1, 13353 Berlin, Germany.

(1) Background: Surveillance of at-risk patients for hepatocellular carcinoma (HCC) is highly necessary, as curative treatment options are only feasible in early disease stages. However, to date, screening of patients with liver cirrhosis for HCC mostly relies on suboptimal ultrasound-mediated evaluation and α-fetoprotein (AFP) measurement. Therefore, we sought to develop a novel and blood-based scoring tool for the identification of early-stage HCC. (2) Methods: Serum samples from 267 patients with liver cirrhosis, including 122 patients with HCC and 145 without, were collected. Expression levels of soluble platelet-derived growth factor receptor beta (sPDGFRβ) and routine clinical parameters were evaluated, and then utilized in logistic regression analysis. (3) Results: We developed a novel serological scoring tool, the APAC score, consisting of the parameters age, sPDGFRβ, AFP, and creatinine, which identified patients with HCC in a cirrhotic population with an AUC of 0.9503, which was significantly better than the GALAD score (AUC: 0.9000, = 0.0031). Moreover, the diagnostic accuracy of the APAC score was independent of disease etiology, including alcohol (AUC: 0.9317), viral infection (AUC: 0.9561), and NAFLD (AUC: 0.9545). For the detection of patients with (very) early (BCLC 0/A) HCC stage or within Milan criteria, the APAC score achieved an AUC of 0.9317 (sensitivity: 85.2%, specificity: 89.2%) and 0.9488 (sensitivity: 91.1%, specificity 85.3%), respectively. (4) Conclusions: The APAC score is a novel and highly accurate serological tool for the identification of HCC, especially for early stages. It is superior to the currently proposed blood-based algorithms, and has the potential to improve surveillance of the at-risk population.
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http://dx.doi.org/10.3390/jcm10153392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348918PMC
July 2021

Hypothermic Oxygenated Machine Perfusion Reduces Early Allograft Injury and Improves Post-transplant Outcomes in Extended Criteria Donation Liver Transplantation From Donation After Brain Death: Results From a Multicenter Randomized Controlled Trial (HOPE ECD-DBD).

Ann Surg 2021 11;274(5):705-712

Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany.

Objective: The aim of this study was to evaluate peak serum alanine aminotransferase (ALT) and postoperative clinical outcomes after hypothermic oxygenated machine perfusion (HOPE) versus static cold storage (SCS) in extended criteria donation (ECD) liver transplantation (LT) from donation after brain death (DBD).

Background: HOPE might improve outcomes in LT, particularly in high-risk settings such as ECD organs after DBD, but this hypothesis has not yet been tested in a randomized controlled clinical trial (RCT).

Methods: Between September 2017 and September 2020, 46 patients undergoing ECD-DBD LT from four centers were randomly assigned to HOPE (n = 23) or SCS (n = 23). Peak-ALT levels within 7 days following LT constituted the primary endpoint. Secondary endpoints included incidence of postoperative complications [Clavien-Dindo classification (CD), Comprehensive Complication Index (CCI)], length of intensive care- (ICU) and hospital-stay, and incidence of early allograft dysfunction (EAD).

Results: Demographics were equally distributed between both groups [donor age: 72 (IQR: 59-78) years, recipient age: 62 (IQR: 55-65) years, labMELD: 15 (IQR: 9-25), 38 male and 8 female recipients]. HOPE resulted in a 47% decrease in serum peak ALT [418 (IQR: 221-828) vs 796 (IQR: 477-1195) IU/L, P = 0.030], a significant reduction in 90-day complications [44% vs 74% CD grade ≥3, P = 0.036; 32 (IQR: 12-56) vs 52 (IQR: 35-98) CCI, P = 0.021], and shorter ICU- and hospital-stays [5 (IQR: 4-8) vs 8 (IQR: 5-18) days, P = 0.045; 20 (IQR: 16-27) vs 36 (IQR: 23-62) days, P = 0.002] compared to SCS. A trend toward reduced EAD was observed for HOPE (17% vs 35%; P = 0.314).

Conclusion: This multicenter RCT demonstrates that HOPE, in comparison to SCS, significantly reduces early allograft injury and improves post-transplant outcomes in ECD-DBD liver transplantation.
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http://dx.doi.org/10.1097/SLA.0000000000005110DOI Listing
November 2021

Liver Injury and the Macrophage Issue: Molecular and Mechanistic Facts and Their Clinical Relevance.

Int J Mol Sci 2021 Jul 6;22(14). Epub 2021 Jul 6.

Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité University Medicine Berlin, 13353 Berlin, Germany.

The liver is an essential immunological organ due to its gatekeeper position to bypassing antigens from the intestinal blood flow and microbial products from the intestinal commensals. The tissue-resident liver macrophages, termed Kupffer cells, represent key phagocytes that closely interact with local parenchymal, interstitial and other immunological cells in the liver to maintain homeostasis and tolerance against harmless antigens. Upon liver injury, the pool of hepatic macrophages expands dramatically by infiltrating bone marrow-/monocyte-derived macrophages. The interplay of the injured microenvironment and altered macrophage pool skews the subsequent course of liver injuries. It may range from complete recovery to chronic inflammation, fibrosis, cirrhosis and eventually hepatocellular cancer. This review summarizes current knowledge on the classification and role of hepatic macrophages in the healthy and injured liver.
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http://dx.doi.org/10.3390/ijms22147249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306699PMC
July 2021

Predicting survival after TIPS: Child Pugh score is not inferior to MELD and FIPS score - back to basics?

J Hepatol 2021 Jul 12. Epub 2021 Jul 12.

Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum and Charité Campus Mitte, Berlin, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2021.07.006DOI Listing
July 2021

Levels of Circulating PD-L1 Are Decreased in Patients with Resectable Cholangiocarcinoma.

Int J Mol Sci 2021 Jun 18;22(12). Epub 2021 Jun 18.

Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.

Tumor resection represents the only curative treatment option for patients with biliary tract cancers (BTCs), including intrahepatic cholangiocarcinoma (CCA), perihilar and extrahepatic CCA and gallbladder cancer. However, many patients develop early tumor recurrence and are unlikely to benefit from surgery. Therefore, markers to identify ideal surgical candidates are urgently needed. Circulating programmed cell death 1 ligand 1 (PD-L1) has recently been associated with different malignancies, including pancreatic cancer which closely resembles BTC in terms of patients' prognosis and tumor biology. Here, we aim at evaluating a potential role of circulating PD-L1 as a novel biomarker for resectable BTC.

Methods: Serum levels of PD-L1 were analyzed by ELISA in 73 BTC patients and 42 healthy controls.

Results: Circulating levels of preoperative PD-L1 were significantly lower in patients with BTC compared to controls. Patients with low PD-L1 levels displayed a strong trend towards an impaired prognosis, and circulating PD-L1 was negatively correlated with experimental markers of promalignant tumor characteristics such as CCL1, CCL21, CCL25 and CCL26. For 37 out of 73 patients, postoperative PD-L1 levels were available. Interestingly, after tumor resection, circulating PD-L1 raised to almost normal levels. Notably, patients with further decreasing PD-L1 concentrations after surgery showed a trend towards an impaired postoperative outcome.

Conclusion: Circulating PD-L1 levels were decreased in patients with resectable BTC. Lack of normalization of PD-L1 levels after surgery might identify patients at high risk for tumor recurrence or adverse outcome.
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http://dx.doi.org/10.3390/ijms22126569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233871PMC
June 2021

The Role of Microbiota in Primary Sclerosing Cholangitis and Related Biliary Malignancies.

Int J Mol Sci 2021 Jun 28;22(13). Epub 2021 Jun 28.

Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.

Primary sclerosing cholangitis (PSC) is an immune-related cholangiopathy characterized by biliary inflammation, cholestasis, and multifocal bile duct strictures. It is associated with high rates of progression to end-stage liver disease as well as a significant risk of cholangiocarcinoma (CCA), gallbladder cancer, and colorectal carcinoma. Currently, no effective medical treatment with an impact on the overall survival is available, and liver transplantation is the only curative treatment option. Emerging evidence indicates that gut microbiota is associated with disease pathogenesis. Several studies analyzing fecal and mucosal samples demonstrate a distinct gut microbiome in individuals with PSC compared to healthy controls and individuals with inflammatory bowel disease (IBD) without PSC. Experimental mouse and observational human data suggest that a diverse set of microbial functions may be relevant, including microbial metabolites and bacterial processing of pharmacological agents, bile acids, or dietary compounds, altogether driving the intrahepatic inflammation. Despite critical progress in this field over the past years, further functional characterization of the role of the microbiota in PSC and related malignancies is needed. In this review, we discuss the available data on the role of the gut microbiome and elucidate important insights into underlying pathogenic mechanisms and possible microbe-altering interventions.
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http://dx.doi.org/10.3390/ijms22136975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268159PMC
June 2021

Donor-Specific Antibodies Against Donor Human Leukocyte Antigen are Associated with Graft Inflammation but Not with Fibrosis Long-Term After Liver Transplantation: An Analysis of Protocol Biopsies.

J Inflamm Res 2021 23;14:2697-2712. Epub 2021 Jun 23.

Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Berlin, Germany.

Background: Donor-specific antibodies (DSA) against donor human leukocyte antigen after liver transplantation, which are associated with histological changes, have been widely studied with respect to their sustained impact on transplant function. However, their long-term impact after liver transplantation remains unclear.

Methods: We performed a cross-sectional analysis from June 2016 to July 2017 that included all patients who presented themselves for scheduled follow-up after receiving a liver transplantation between September 1989 and December 2016. In addition to a liver protocol biopsy, patients were screened for human leukocyte antigen antibodies (HLAab) and donor-specific antibodies. Subsequently, the association between human leukocyte antigen antibodies, donor-specific antibodies, histologic and clinical features, and immunosuppression was analyzed.

Results: Analysis for human leukocyte antigen antibodies and donor-specific antibodies against donor human leukocyte antigen was performed for 291 and 271 patients. A significant association between higher inflammation grades and the presence of human leukocyte antigen antibodies and donor-specific antibodies was detected, while fibrosis stages remained unaffected. These results were confirmed by multivariate logistic regression for inflammation showing a significant increase for presence of human leukocyte antigen antibodies and donor-specific antibodies (OR: 4.43; 95% CI: 1.67-12.6; p=0.0035). Furthermore, the use of everolimus in combination with tacrolimus was significantly associated with the status of negative human leukocyte antigen antibodies and donor-specific antibodies. Viral etiology for liver disease, hepatocellular carcinoma (HCC) and higher steatosis grades of the graft were significantly associated with a lower rate of human leukocyte antigen antibodies. The impact of human leukocyte antigen antibodies and donor-specific antibodies against donor human leukocyte antigen was associated with higher levels of laboratory parameters, such as transaminases and bilirubin.

Conclusion: Donor-specific antibodies against donor human leukocyte antigen are associated with histological and biochemical graft inflammation after liver transplantation, while fibrosis seems to be unaffected. Future studies should validate these findings for longer observation periods and specific subgroups.
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http://dx.doi.org/10.2147/JIR.S307778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236257PMC
June 2021

Editorial: Overcoming the Immune Microenvironment of Hepatocellular Cancer.

Front Immunol 2021 2;12:707329. Epub 2021 Jun 2.

Department of Hepatology & Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

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http://dx.doi.org/10.3389/fimmu.2021.707329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208027PMC
June 2021

Atezolizumab and bevacizumab-induced encephalitis in advanced hepatocellular carcinoma: Case report and literature review.

Medicine (Baltimore) 2021 06;100(24):e26377

Department of Hepatology and Gastroenterology.

Introduction: On the basis of the results of the IMBRAVE-150 trial, the combination of atezolizumab, a programmed cell death ligand 1 (PD-L1) antibody, as well as bevacizumab, a vascular endothelial growth factor (VEGF) antibody, represents a promising novel first-line therapy in patients with advanced hepatocellular carcinoma (HCC). Despite favorable safety data, serious adverse events have been described. However, central nervous system complications such as encephalitis have rarely been reported. We present the case of a 70-year-old woman with hepatitis C virus (HCV)-related liver cirrhosis and advanced HCC who developed severe encephalitis after only one cycle of atezolizumab/bevacizumab.

Patient Concerns: Ten days after administration, the patient presented with confusion, somnolence, and emesis. Within a few days, the patient's condition deteriorated, and mechanical ventilation became necessary.

Diagnosis: Cerebrospinal fluid (CSF) analysis showed increased cell count and elevated protein values. Further work-up revealed no signs of an infectious, paraneoplastic, or other autoimmune cause.

Intervention: Suspecting an atezolizumab/bevacizumab-related encephalitis, we initiated a high-dose steroid pulse therapy as well as repeated plasmapheresis, which resulted in clinical improvement and remission of CSF abnormalities.

Outcome: Despite successful weaning and transfer to a rehabilitation ward, the patient died of progressive liver cancer 76 days after initial treatment with atezolizumab/bevacizumab, showing no response.

Conclusion: This case illustrates that rapid immunosuppressive treatment with prednisolone can result in remission even of severe encephalitis. We discuss this case in the context of available literature and previously reported cases of atezolizumab-induced encephalitis in different tumor entities, highlighting the diagnostic challenges in oncologic patients treated with immune checkpoint-inhibitors.
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http://dx.doi.org/10.1097/MD.0000000000026377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213300PMC
June 2021

Pharmacotherapy Profiles in People with Opioid Use Disorders: Considerations for Relevant Drug-Drug Interactions with Antiviral Treatments for Hepatitis C.

Pathogens 2021 May 24;10(6). Epub 2021 May 24.

Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, 10117 Berlin, Germany.

People who inject drugs (PWID) are often affected by physical and psychological diseases and prone to co-medication. In Germany, about 50% of PWID are on opioid substitution therapy (OST). Comprehensive data on pharmacotherapy in these patients may help to select antiviral therapy against hepatitis C virus (HCV) infections and avoid drug-drug interactions (DDIs). We compared co-medication profiles based on statutory health insurance prescriptions (IQVIA database) of PWID (n = 16,693), OST (n = 95,023) and treated HCV patients (n = 7886). Potential DDIs with the most widely used HCV direct-acting agents (Sofosbuvir/Velpatasvir, Glecaprevir/Pibrentasvir and Elbasvir/Grazoprevir) were evaluated based on the Liverpool DDI database. Co-medication was present in 57% of PWID, 57% of OST, 44% of patients on HCV therapy and 46% in a subgroup receiving OST+HCV therapy (n = 747 of 1613). For all groups, co-medication belonging to ATC-class N (nervous system) was most commonly prescribed (in 75%, 68%, 41% and 62% of patients, respectively). Contraindications (i.e., DDIs precluding HCV therapy) were infrequent (0.4-2.5% of co-medications); potential DDIs with HCV therapies were shown for 13-19% of co-medications, namely for specific substances including some analgesics, antipsychotics, anticoagulants, lipid lowering drugs and steroids. In conclusion, concomitant pharmacotherapy is common and clinically relevant when treating HCV infection in PWID.
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http://dx.doi.org/10.3390/pathogens10060648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225070PMC
May 2021

Shear Wave Elastography in the Detection of Sinusoidal Obstruction Syndrome in Adult Patients Undergoing Allogenic Hematopoietic Stem Cell Transplantation.

Diagnostics (Basel) 2021 May 21;11(6). Epub 2021 May 21.

Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), 13353 Berlin, Germany.

Hepatic sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD) can be a life-threatening complication after hematopoietic stem cell transplantation (HSCT). Diagnosis is often difficult and traditionally based on clinical parameters. Shear wave elastography (SWE) is a modern non-invasive liver stiffness measurement technique using ultrasound. In this monocentric study, we evaluated the role of SWE in diagnosing SOS/VOD in 63 adult patients undergoing HSCT from February 2020 to August 2020 in real world settings. Three patients developed SOS/VOD. This was accompanied by an increase in shear wave velocity in all three patients, indicating that this method may contribute to establishing the diagnosis SOS/VOD after HSCT.
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http://dx.doi.org/10.3390/diagnostics11060928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224360PMC
May 2021

Vaccination as a Strategy to Modulate the Immune Microenvironment of Hepatocellular Carcinoma.

Front Immunol 2021 7;12:650486. Epub 2021 May 7.

Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany.

Hepatocellular Carcinoma (HCC) is a highly prevalent malignancy that develops in patients with chronic liver diseases and dysregulated systemic and hepatic immunity. The tumor microenvironment (TME) contains tumor-associated macrophages (TAM), cancer-associated fibroblasts (CAF), regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) and is central to mediating immune evasion and resistance to therapy. The interplay between these cells types often leads to insufficient antigen presentation, preventing effective anti-tumor immune responses. vaccines harness the tumor as the source of antigens and implement sequential immunomodulation to generate systemic and lasting antitumor immunity. Thus, vaccines hold the promise to induce a switch from an immunosuppressive environment where HCC cells evade antigen presentation and suppress T cell responses towards an immunostimulatory environment enriched for activated cytotoxic cells. Pivotal steps of vaccination include the induction of immunogenic cell death of tumor cells, a recruitment of antigen-presenting cells with a focus on dendritic cells, their loading and maturation and a subsequent cross-priming of CD8+ T cells to ensure cytotoxic activity against tumor cells. Several vaccine approaches have been suggested, with vaccine regimens including oncolytic viruses, Flt3L, GM-CSF and TLR agonists. Moreover, combinations with checkpoint inhibitors have been suggested in HCC and other tumor entities. This review will give an overview of various vaccine strategies for HCC, highlighting the potentials and pitfalls of vaccines to treat liver cancer.
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http://dx.doi.org/10.3389/fimmu.2021.650486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137829PMC
September 2021

Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH)-related liver fibrosis: mechanisms, treatment and prevention.

Ann Transl Med 2021 Apr;9(8):729

Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany.

Liver fibrosis is the excessive expression and accumulation of extracellular matrix proteins in the liver. Fibrotic scarring occurs as the consequence of chronic injury and inflammation. While the successful treatment of hepatitis B and C reduced the burden of liver disease related to viral hepatitis, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) are nowadays the leading causes of hepatic fibrosis worldwide. Although basic research activities have significantly advanced our understanding of the molecular disease pathogenesis, the present therapeutic options for fibrosis are still limited. In advanced disease stages, liver transplantation often remains the only curative treatment. This highlights the necessity of preventive strategies to avoid complications of fibrosis, particularly cirrhosis, portal hypertension and liver cancer. Lifestyle modifications (weight loss, exercise, healthy diet) are the basis for prevention and treatment of NAFLD-associated fibrosis. In the present review, we discuss recent advances in antifibrotic prevention and therapy. In particular, we review the current concepts for antifibrotic drug candidates in the treatment of NAFLD and NASH. While some compounds aim at reverting pathogenic liver metabolism, an alternative approach is to disconnect the injury (e.g., NAFLD) from inflammation and/or fibrosis. Investigational drugs typically target metabolic pathways, insulin resistance, hepatocyte death, inflammatory cell recruitment or activation, the gut-liver axis, matrix expression or matrix turnover. While several promising drug candidates failed in phase 2 or 3 clinical trials (including elafibranor, emricasan and selonsertib), promising results with the farnesoid X receptor agonist obeticholic acid, the pan-PPAR agonist lanifibranor and the chemokine receptor CCR2/CCR5 inhibitor cenicriviroc support the expectation of an effective pharmacological therapy for liver fibrosis in the near future. Tackling NAFLD-associated fibrosis from different directions by combinatorial drug treatment and effective lifestyle changes hold the greatest prospects.
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http://dx.doi.org/10.21037/atm-20-4354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106094PMC
April 2021

An Unexpected Line of Defense: Hepatoprotective Eosinophils in Ischemia-Reperfusion Injury.

Hepatology 2021 May 11. Epub 2021 May 11.

Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.

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http://dx.doi.org/10.1002/hep.31895DOI Listing
May 2021
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