Publications by authors named "Ansgar W Lohse"

332 Publications

A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease.

N Engl J Med 2021 07;385(1):35-45

From the Institute of Translational Immunology and Celiac Center, Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University, Mainz (D.S., T.F.-S.), the Department of Internal and Integrative Medicine, Sozialstiftung Bamberg, Bamberg (J.L.), the Department of Integrative Medicine, University of Duisburg-Essen, Duisburg-Essen (J.L.), the Division of Gastroenterology, Hepatology, and Infectious Diseases, Department of Internal Medicine I, University Hospital Tübingen, Tübingen (S.F.), the Department of Gastroenterology, Infectious Diseases, and Rheumatology, Campus Benjamin Franklin, Charité-University Medicine Berlin, Berlin (M. Schumann), the Department of Medicine II, University Hospital, Ludwig Maximilians University, Munich (H.P.T.), the Department of Medicine 1, Hector Center for Nutrition, Exercise, and Sports, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen (Y.Z.), the Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg (A.W.L.), the Department of Internal Medicine IV, University Hospital, Friedrich-Schiller University Jena, Jena (A.S.), and Dr. Falk Pharma, Freiburg (R.M., R.G.) - all in Germany; the Division of Gastroenterology and Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston (D.S.); the Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital (M.M., A.P., M.-L.L.), the Faculty of Medicine and Health Technology, Tampere University (J.I., J.T.), Jilab (J.I.), and the Department of Pediatrics, Tampere University Hospital (M.-L.L.), Tampere, the Department of Internal Medicine, Central Finland Central Hospital, Jyväskylä (J.T.), Lääkärikeskus Aava Helsinki Kamppi, Helsinki (J. Koskenpato), and Clinical Research Services Turku, Turku (M. Scheinin) - all in Finland; Oslo University Hospital, Rikshospitalet, and Stiftelsen K.G. Jebsen Celiac Disease Research Center, University of Oslo, Oslo (K.E.A.L.), the Medical Department, Innlandet Hospital Trust, Gjøvik (O.H.), and Akershus University Hospital, Lørenskog (J.J.) - all in Norway; the University of Medicine and Pharmacy "Carol Davila" and the National Institute for Mother and Child Health "Alessandrescu-Rusescu," Bucharest, Romania (A.P.); the Gastroenterology Department and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania (J. Kupcinskas); the Department of Gastroenterology, Internal Medicine Clinic, Tartu University Hospital, Tartu, Estonia (K.K.); the Department of Gastroenterology and Hepatology, University Hospital Zurich (L.B., J.Z.), and the Swiss Celiac Center, Center of Gastroenterology, Clinic Hirslanden (J.Z.) - both in Zurich, Switzerland; and University College Hospital Galway, Galway, Ireland (V.B.).

Background: In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal injury. Inhibition of transglutaminase 2 is a potential treatment for celiac disease.

Methods: In a proof-of-concept trial, we assessed the efficacy and safety of a 6-week treatment with ZED1227, a selective oral transglutaminase 2 inhibitor, at three dose levels as compared with placebo, in adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point was the attenuation of gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Secondary end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score (for assessment of health-related quality of life).

Results: Of the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P = 0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001). The estimated differences from placebo in the change in intraepithelial lymphocyte density were -2.7 cells per 100 epithelial cells (95% CI, -7.6 to 2.2) in the 10-mg group, -4.2 cells per 100 epithelial cells (95% CI, -8.9 to 0.6) in the 50-mg group, and -9.6 cells per 100 epithelial cells (95% CI, -14.4 to -4.8) in the 100-mg group. Use of the 100-mg dose may have improved symptom and quality-of-life scores. The most common adverse events, the incidences of which were similar across all groups, were headache, nausea, diarrhea, vomiting, and abdominal pain. Rash developed in 3 of 40 patients (8%) in the 100-mg group.

Conclusions: In this preliminary trial, treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease. (Funded by Dr. Falk Pharma; CEC-3 EudraCT number, 2017-002241-30.).
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http://dx.doi.org/10.1056/NEJMoa2032441DOI Listing
July 2021

Performance of non-invasive fibrosis scores in non-alcoholic fatty liver disease with and without morbid obesity.

Int J Obes (Lond) 2021 Jun 24. Epub 2021 Jun 24.

I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Non-invasive scores, such as the non-alcoholic fatty liver disease (NAFLD) Fibrosis Score (NFS), are increasingly used for liver fibrosis assessment in patients with NAFLD. The aim of this study was to assess the applicability and reliability of non-invasive fibrosis scores in NAFLD patients with and without morbid obesity.

Methods: Three hundred sixty-eight patients with biopsy-proven NAFLD identified between January 2012 and December 2015 were studied; 225 with morbid obesity (biopsy obtained during bariatric surgery) and 143 patients without (termed as "conventional").

Results: Median age was 47 years, 57% were female. Median body mass index (BMI) was 42.9 kg/m with significant differences between our conventional and morbidly obese patients (BMI 29.0 vs. 50.8 kg/m, p < 0.001). Overall, 42% displayed mild/moderate and 16% advanced liver fibrosis (stage III/IV). All tested scores were significantly linked to fibrosis stage (p < 0.001 for all). FIB-4 (AUROC 0.904), APRI (AUROC 0.848), and NFS (AUROC 0.750) were identified as potent predictors of advanced fibrosis, although NFS overestimated fibrosis stage in morbid obesity. Limiting BMI to a maximum of 40 kg/m improved NFS' overall performance (AUROC 0.838). FIB-4 > 1.0 indicated high probability of advanced fibrosis (OR = 29.1). FIB-4 predicted advanced fibrosis independently from age, sex, BMI, and presence of morbid obesity.

Conclusions: Our data suggest that FIB-4 score is an accurate predictor of advanced fibrosis in NAFLD throughout all BMI stages. Without adjustment, NFS tends to overestimate fibrosis in morbidly obese NAFLD patients. This problem may be solved by implementation of an upper BMI limit (for NFS) or adjustment of diagnostic thresholds.
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http://dx.doi.org/10.1038/s41366-021-00881-8DOI Listing
June 2021

Prevalence and risk factors of undiagnosed diabetes mellitus among gastroenterological patients: a HbA1c-based single center experience.

Z Gastroenterol 2021 Jun 22. Epub 2021 Jun 22.

I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Diabetes mellitus is a major risk factor for microvascular disease, leading to chronic kidney injury or cardiovascular disease, but there is a tremendous proportion of patients worldwide who suffer from undiagnosed diabetes. Until now, little is known about the prevalence of undiagnosed diabetes in gastroenterology inpatients.

Objective: To improve detection of undiagnosed diabetes, a routine screening procedure for gastroenterology inpatients, based on hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) measurement, was established.

Methods: We conducted a retrospective analysis of the implemented diabetes screening. Diabetes mellitus was diagnosed according to the guideline of the German Diabetes Association in patients with an HbA1c of ≥6.5% anld/or fasting plasma glucose (FPG) ≥126 mg/dL. Univariate and multivariate analyses were performed to identify independent risk factors for undiagnosed diabetes.

Results: Within a 3-month period, 606 patients were eligible for a diabetes screening. Pre-existing diabetes was documented in 120 patients (19.8 %), undiagnosed diabetes was found in 24 (3.9%), and 162 patients (26.7%) met the definition for prediabetes. Steroid medication use, age, and liver cirrhosis due to primary sclerosing cholangitis (PSC) were identified as risk factors for undiagnosed diabetes.

Conclusion: The prevalence of undiagnosed diabetes in gastroenterology inpatients is markedly elevated in comparison to the general population, and a substantial number of inpatients are in a prediabetic status, underlining the need for diabetes screening. In addition to previously described risk factors of patient age and steroid medication use, we identified PSC-related liver cirrhosis (but not liver cirrhosis due to another etiology) as an independent risk factor for undiagnosed diabetes.
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http://dx.doi.org/10.1055/a-1482-8840DOI Listing
June 2021

Drug-induced liver injury at a tertiary care centre in Germany: Model for end-stage liver disease is the best predictor of outcome.

Liver Int 2021 Jun 21. Epub 2021 Jun 21.

I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

Background & Aims: Agents most frequently inducing idiosyncratic drug-induced liver injury (DILI) differ between countries worldwide. Besides, there is no consistent data on the best model predicting mortality or the need for liver transplantation in DILI. We here analysed the DILI cohort of our centre with regard to causative drugs and clinical outcome.

Methods: A retrospective analysis of 157 consecutive severe DILI patients presenting to our tertiary care centre in Hamburg, Germany, from 2008 to 2018, was performed.

Results: The most frequent putatively causative drugs were phenprocoumon (n = 21), metamizole (n = 17) and flupirtine (n = 6). The mean values of ALT, bilirubin and Model for End-stage Liver Disease (MELD) score at the time of hospitalisation were 1201 U/L (SD: 1169 U/L), 6.8 mg/dL (SD: 7 mg/dL) and 17 (SD: 8). About 71% of all cases were treated with steroids or steroids combined with n-acetylcysteine. About 12.1% of all DILI cases had a poor outcome (liver transplantation and/or death). At the time of admission, MELD score performed better than Hy's law, the ratio (R) or the new ratio (nR) on their own or combined with bilirubin, regarding sensitivity or specificity for poor outcome. MELD score had a c-statistic of 0.847 (95% CI: 0.731-0.964). Furthermore, the cut-off of 18 MELD points had a sensitivity of 88% and a specificity of 72% for poor outcome.

Conclusion: Phenprocoumon and metamizole are frequent causative drugs for DILI in Germany. In comparison to other prognostic scores, MELD score ≥18 at the time of admission performed best in our cohort for the prediction of poor outcome in DILI.
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http://dx.doi.org/10.1111/liv.14985DOI Listing
June 2021

Cardiovascular magnetic resonance demonstrates structural cardiac changes following transjugular intrahepatic portosystemic shunt.

Sci Rep 2021 Jun 16;11(1):12719. Epub 2021 Jun 16.

I. Department of Medicine, Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Transjugular intrahepatic portosystemic shunt (TIPS) reduces portal hypertension in patients with liver cirrhosis. The exact cardiac consequences of subsequent increase of central blood volume are unknown. Cardiovascular magnetic resonance (CMR) imaging is the method of choice for quantifying cardiac volumes and ventricular function. The aim of this study was to investigate effects of TIPS on the heart using CMR, laboratory, and imaging cardiac biomarkers. 34 consecutive patients with liver cirrhosis were evaluated for TIPS. Comprehensive CMR with native T1 mapping, transthoracic echocardiography, and laboratory biomarkers were assessed before and after TIPS insertion. Follow-up (FU) CMR was obtained in 16 patients (47%) 207 (170-245) days after TIPS. From baseline (BL) to FU, a significant increase of all indexed cardiac chamber volumes was observed (all P < 0.05). Left ventricular (LV) end-diastolic mass index increased significantly from 45 (38-51) to 65 (51-73) g/m (P =  < 0.01). Biventricular systolic function, NT-proBNP, high-sensitive troponin T, and native T1 time did not differ significantly from BL to FU. No patient experienced cardiac decompensation following TIPS. In conclusion, in patients without clinically significant prior heart disease, increased cardiac preload after TIPS resulted in increased volumes of all cardiac chambers and eccentric LV hypertrophy, without leading to cardiac impairment during follow-up in this selected patient population.
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http://dx.doi.org/10.1038/s41598-021-92064-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209000PMC
June 2021

Prevalence of COVID-19 in patients with autoimmune liver disease in Europe: A patient-oriented online survey.

United European Gastroenterol J 2021 Jun 9. Epub 2021 Jun 9.

I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

Background: During the current SARS-CoV-2 pandemic it is important to identify risk factors for COVID-19. Registry studies are providing growing evidence on the elevated risk of mortality from COVID-19 in patients with chronic liver disease, especially in advanced stages. Results may, however, have a selection bias towards severe cases. Limited data is available on COVID-19 in patients with autoimmune liver disease (AILD).

Aim: To perform an online survey to capture the prevalence of COVID-19 and the state of medical care of patients with AILD in Europe during the pandemic.

Methods: Data was collected via an anonymous patient-oriented, online survey, which was available on the EUSurvey platform in nine European languages between 24 June 2020 and 14 October 2020. Of 1834 contributions, 51 were excluded because participants did not name an underlying AILD, and four were excluded because of duplicate data entry.

Results: Of 1,779 participants, 1,752 resided in 20 different countries of the European Union and the United Kingdom (UK). The five countries with the highest numbers of contributions were France (n = 450), Germany (n = 318), the Netherlands (n = 267), Spain (n = 225), and the UK (n = 183). 2.2% of participants (39/1779) had been diagnosed with COVID-19. There were no differences regarding age, sex, AILD, the status of liver cirrhosis, or status post liver transplantation between COVID-19 and non-COVID-19 cases. Of the 39 COVID-19 cases, five patients were admitted to a regular ward, one patient was admitted to ICU and required ventilation.

Conclusion: In our Europe-wide, patient-oriented survey on COVID-19 in patients with AILD, we detected a low rate of COVID-19, comparable to the period prevalence of the general population. These results suggest that patients with AILD are not at elevated risk of COVID-19.
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http://dx.doi.org/10.1002/ueg2.12100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242670PMC
June 2021

Patient Characteristics and Clinical Course of COVID-19 Patients Treated at a German Tertiary Center during the First and Second Waves in the Year 2020.

J Clin Med 2021 May 24;10(11). Epub 2021 May 24.

I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.

In this study, we directly compared coronavirus disease 2019 (COVID-19) patients hospitalized during the first (27 February-28 July 2020) and second (29 July-31 December 2020) wave of the pandemic at a large tertiary center in northern Germany. Patients who presented during the first ( = 174) and second ( = 331) wave did not differ in age (median [IQR], 59 years [46, 71] vs. 58 years [42, 73]; = 0.82) or age-adjusted Charlson Comorbidity Index (median [IQR], 2 [1, 4] vs. 2 [0, 4]; = 0.50). During the second wave, a higher proportion of patients were treated as outpatients (11% [ = 20] vs. 20% [ = 67]), fewer patients were admitted to the intensive care unit (43% [ = 75] vs. 29% [ = 96]), and duration of hospitalization was significantly shorter (median days [IQR], 14 [8, 34] vs. 11 [5, 19]; < 0.001). However, in-hospital mortality was high throughout the pandemic and did not differ between the two periods (16% [ = 27] vs. 16% [ = 54]; = 0.89). While novel treatment strategies and increased knowledge about the clinical management of COVID-19 may have resulted in a less severe disease course in some patients, in-hospital mortality remained unaltered at a high level. These findings highlight the unabated need for efforts to hamper severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) transmission, to increase vaccination coverage, and to develop novel treatment strategies to prevent mortality and decrease morbidity.
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http://dx.doi.org/10.3390/jcm10112274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197386PMC
May 2021

Diagnostic and Prognostic Value of miR-16, miR-146a, miR-192 and miR-221 in Exosomes of Hepatocellular Carcinoma and Liver Cirrhosis Patients.

Cancers (Basel) 2021 May 19;13(10). Epub 2021 May 19.

Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

We aimed to identify a specific microRNA (miRNA) pattern to determine diagnostic and prognostic value in plasma exosomes of hepatocellular carcinoma (HCC) patients. A two-stage study was carried out: exosomal miRNAs were quantified in plasma of HCC patients and healthy individuals by PCR-based microarray cards containing 45 different miRNAs (training cohort). Then, four deregulated miRNAs (miR-16, miR-146a, miR-192, and miR-221) were quantified in the validation analysis using exosomes derived from 85 HCC patients, 50 liver cirrhosis patients, and 20 healthy individuals. Exosomal miR-146a ( = 0.0001), miR-192 ( = 0.002) and miR-221 ( = 0.032) were upregulated only in HCC patients. Repeated 10-fold cross validation showed that miR-146a differentiated HCC from liver cirrhosis patients with AUC of 0.80 ± 0.14 (sensitivity: 81 ± 13%, specificity: 58 ± 22%) in a logistic regression model. High miR-192 presence is associated with poor overall survival (OS) in all HCC patients ( = 0.027) and was predictor of OS in HCC patients in an uni- and multivariate Cox regression model. Moreover, decreased miR-16 levels correlated with OS in liver cirrhosis patients ( = 0.034). Our results emphasized that exosomes secreted into the plasma carry differentially expressed miRNAs of which in particular, miR-192, miR-146, and miR-16 are promising diagnostic and prognostic markers for both HCC and liver cirrhosis patients.
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http://dx.doi.org/10.3390/cancers13102484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161187PMC
May 2021

Evolution of liver stiffness and post-treatment surveillance by liver elastography for HCV patients in the DAA era.

Scand J Gastroenterol 2021 Jul 19;56(7):840-848. Epub 2021 May 19.

I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objective: Baseline liver stiffness (LS) is prognostically relevant in patients with chronic hepatitis C virus (HCV) infection but may change after successful HCV eradication. Data on post-treatment LS for a further risk stratification remain scarce. Here, we study the kinetics of LS and laboratory parameters in patients undergoing HCV treatment and analyze the association of post-treatment LS with outcome parameters.

Methods: In a cohort of 1011 chronic HCV patients undergoing DAA treatment, we identified 404 patients with sequential LS and laboratory assessments with or without viral eradication. Additionally, outcome parameters were correlated with post-treatment LS after successful HCV therapy.

Results: LS significantly decreased from a median of 8.8 to 6.1 kPa in 346 patients after HCV eradication, but significantly increased from a median of 10.5 to 11.9 kPa in 58 patients without viral clearance. In 78 patients with two sequential post-treatment measurements, LS decreased from 12.6 to 8.7 kPa after a median 344 d, with a further decrease to 7.0 kPa after a median of 986 d after end of treatment (EoT). In 400 patients with a post-treatment LS assessment after viral eradication, only 9 liver-related events occurred over a median follow-up (FU) of 23 months. All events were observed in patients with a post-treatment LS >20 kPa.

Conclusions: After successful HCV eradication, LS improves sequentially, suggesting an initial phase of necroinflammation regression followed by a second phase of true fibrosis regression. Overall, liver-related events were rarely observed and seem to be limited to patients with a post-treatment LS >20 kPa, so that these patients require a closer clinical monitoring.
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http://dx.doi.org/10.1080/00365521.2021.1915374DOI Listing
July 2021

Sequential Systemic Treatment in Advanced Hepatocellular Carcinoma Is Able to Prolong Median Survival to More than 3 Years in a Selected Real-World Cohort.

Visc Med 2021 Mar 7;37(2):87-93. Epub 2020 May 7.

I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Introduction: The number of efficacious systemic agents for advanced hepatocellular carcinoma (HCC) has rapidly increased over the past 3 years. However, guidance for optimal sequential systemic treatment in patients with advanced disease and experience with outcome and safety profiles are lacking.

Objective: We aimed to assess efficacy and tolerability of sequential systemic therapy of advanced HCC.

Methods: Our single-center study prospectively followed 14 patients who received multiple, sequential systemic therapies after progression or intolerance to sorafenib. Endpoints were overall and progression-free survival (OS, PFS), objective response rate (ORR), and treatment-emergent adverse events (TEAE).

Results: Patients had well-compensated liver function and good performance status at start of each systemic therapy. Agents included sorafenib ( = 14), regorafenib ( = 10), immunotherapy with nivolumab or pembrolizumab ( = 10), lenvatinib ( = 3), ramucirumab ( = 2), and others, with a median of 3 lines of systemic therapy per patient. Median OS was 37.4 months from initiation of first-line therapy with sorafenib. PFS and ORR for sorafenib, regorafenib, and immunotherapy were 6.6, 5.3, and 6.6 months, and 15.4, 11.1, and 22.2%, respectively. TEAE were frequent (46-80%), but mostly manageable during tyrosine kinase inhibitor therapy and without the need for termination in most patients. However, TEAE due to immunotherapy (60%) led to cessation of treatment in 40% of the patients.

Conclusions: Sequential systemic therapy is able to prolong median OS in selected patients with advanced HCC to more than 3 years. TEAE are frequent, but manageable, and the quality of adverse events depends on the respective agent. Further investigation of potential predictive biomarkers for treatment allocation is needed.
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http://dx.doi.org/10.1159/000507381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077524PMC
March 2021

High Rates of Liver Cirrhosis and Hepatocellular Carcinoma in Chronic Hepatitis B Patients with Metabolic and Cardiovascular Comorbidities.

Microorganisms 2021 Apr 30;9(5). Epub 2021 Apr 30.

Department of Internal Medicine, University Medical Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.

Background: The prevalence of metabolic and cardiovascular diseases is rising worldwide. However, little is known about the impact of such disorders on hepatic disease progression in chronic hepatitis B (CHB) during the era of potent nucleo(s)tide analogues (NAs).

Methods: We retrospectively analyzed a single-center cohort of 602 CHB patients, comparing the frequency of liver cirrhosis at baseline and incidences of liver-related events during follow-up (hepatocellular carcinoma, liver transplantation and liver-related death) between CHB patients with a history of diabetes, obesity, hypertension or coronary heart disease (CHD).

Results: Rates of cirrhosis at baseline and liver-related events during follow-up (median follow-up time: 2.51 years; NA-treated: 37%) were substantially higher in CHB patients with diabetes (11/23; 3/23), obesity (6/13; 2/13), CHD (7/11; 2/11) or hypertension (15/43; 4/43) compared to CHB patients without the indicated comorbidities (26/509; 6/509). Multivariate analysis identified diabetes as the most significant predictor for cirrhosis ( = 0.0105), while comorbidities did not correlate with liver-related events in pre-existing cirrhosis.

Conclusion: The combination of metabolic diseases and CHB is associated with substantially increased rates of liver cirrhosis and secondary liver-related events compared to CHB alone, indicating that hepatitis B patients with metabolic comorbidities warrant particular attention in disease surveillance and evaluation of treatment indication.
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http://dx.doi.org/10.3390/microorganisms9050968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146494PMC
April 2021

SARS-CoV-2 Reinfection in a Healthcare Worker Despite the Presence of Detectable Neutralizing Antibodies.

Viruses 2021 04 12;13(4). Epub 2021 Apr 12.

German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Germany.

So far, only a few reports about reinfections with SARS-CoV-2 have been published, and they often lack detailed immunological and virological data. We report about a SARS-CoV-2 reinfection with a genetically distinct SARS-CoV-2 variant in an immunocompetent female healthcare worker that has led to a mild disease course. No obvious viral escape mutations were observed in the second virus variant. The infectious virus was shed from the patient during the second infection episode despite the presence of neutralizing antibodies in her blood. Our data indicate that a moderate immune response after the first infection, but not a viral escape, did allow for reinfection and live virus shedding.
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http://dx.doi.org/10.3390/v13040661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070424PMC
April 2021

[Early Detection of Psychological Comorbidity in Patients Admitted to Dermatological and Internal Medicine Wards: A New Care Model for Psychosomatic Consultation Service].

Psychother Psychosom Med Psychol 2021 Apr 29. Epub 2021 Apr 29.

Klinik für Psychosomatische Medizin und Psychotherapie, Universitätsklinikum Hamburg-Eppendorf, Deutschland.

This article explains the development and implementation of a psychosomatic screening and consultation service for inpatient somatic care. Approximately one in six somatic inpatients has a mental disorder. It is estimated that only half of these cases are properly identified. Consequently, a large proportion of patients remains untreated. To address this gap in care, a psychosomatic early detection programme was developed by an interdisciplinary working group. This programme is based on the Patient Health Questionnaire-4 (PHQ-4), a psychometrically very well evaluated ultra-short screening questionnaire for the detection of depressive and anxiety disorders. For implementation in routine inpatient care, the PHQ-4 was programmed as a form in the electronic medical record and administered by nursing staff during the admission interview. If the PHQ-4 screening result indicates the presence of a mental comorbidity and the patient expresses a wish for assessment of this disorder, a psychosomatic consultation is automatically ordered. The PHQ-4 was implemented into the clinical routine in four internal medicine and three dermatology wards of the University Medical Center Hamburg-Eppendorf. Documentation of the early diagnosis in the electronic patient record is a minimally costly, less time-consuming and practicable method of providing patients with holistic care through rapid interdisciplinary referral. An evaluation of cost-effectiveness, clinical efficiency, and acceptance is still pending.
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http://dx.doi.org/10.1055/a-1457-3178DOI Listing
April 2021

Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4 T cells in primary sclerosing cholangitis.

J Hepatol 2021 Aug 24;75(2):414-423. Epub 2021 Mar 24.

I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany. Electronic address:

Background & Aims: Little is known about the composition of intrahepatic immune cells and their contribution to the pathogenesis of primary sclerosing cholangitis (PSC). Herein, we aimed to create an atlas of intrahepatic T cells and thereby perform an in-depth characterization of T cells in inflamed human liver.

Methods: Different single-cell RNA sequencing methods were combined with in silico analyses on intrahepatic and peripheral T cells from patients with PSC (n = 11) and healthy donors (HDs, n = 4). Multi-parameter flow cytometry and functional in vitro experiments were conducted on samples from patients with PSC (n = 24), controls with other liver diseases and HDs.

Results: We identified a population of intrahepatic naive-like CD4 T cells, which was present in all liver diseases tested, but particularly expanded in PSC. This population had a transcriptome and T cell receptor repertoire similar to circulating naive T cells but expressed a set of genes associated with tissue residency. Their periductal location supported the concept of tissue-resident naive-like T cells in livers of patients with PSC. Trajectory inference suggested that these cells had the developmental propensity to acquire a T helper 17 (T17) polarization state. Functional and chromatin accessibility experiments revealed that circulating naive T cells in patients with PSC were predisposed to polarize towards T17 cells.

Conclusion: We report the first atlas of intrahepatic T cells in PSC, which led to the identification of a previously unrecognized population of tissue-resident naive-like T cells in the inflamed human liver and to the finding that naive CD4 T cells in PSC harbour the propensity to develop into T17 cells.

Lay Summary: The composition of intrahepatic immune cells in primary sclerosing cholangitis (PSC) and their contribution to disease pathogenesis is widely unknown. We analysed intrahepatic T cells and identified a previously uncharacterized population of liver-resident CD4 T cells which are expanded in the livers of patients with PSC compared to healthy liver tissue and other liver diseases. These cells are likely to contribute to the pathogenesis of PSC and could be targeted in novel therapeutic approaches.
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http://dx.doi.org/10.1016/j.jhep.2021.03.016DOI Listing
August 2021

Bone microarchitecture in patients with autoimmune hepatitis.

J Bone Miner Res 2021 Jul 30;36(7):1316-1325. Epub 2021 Mar 30.

Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

In patients with autoimmune hepatitis (AIH), osteoporosis represents a common extrahepatic complication, which we recently showed by an assessment of areal bone mineral density (aBMD) via dual-energy x-ray absorptiometry (DXA). However, it is well established that bone quality and fracture risk does not solely depend on aBMD, but also on bone microarchitecture. It is currently not known whether AIH patients exhibit a site-specific or compartment-specific deterioration in the skeletal microarchitecture. In order to assess potential geometric, volumetric, and microarchitectural changes, high-resolution peripheral quantitative computed tomography (HR-pQCT) measurements were performed at the distal radius and distal tibia in female patients with AIH (n = 51) and compared to age-matched female healthy controls (n = 32) as well as to female patients with AIH/primary biliary cholangitis (PBC) overlap syndrome (n = 25) and female patients with PBC alone (PBC, n = 36). DXA at the lumbar spine and hip, clinical characteristics, transient elastography (FibroScan) and laboratory analyses were also included in this analysis. AIH patients showed a predominant reduction of cortical thickness (Ct.Th) in the distal radius and tibia compared to healthy controls (p < .0001 and p = .003, respectively). In contrast, trabecular parameters such as bone volume fraction (BV/TV) did not differ significantly at the distal radius (p = .453) or tibia (p = .508). Linear regression models revealed significant negative associations between age and Ct.Th (95% confidence interval [CI], -14 to -5 μm/year, p < .0001), but not between liver stiffness, cumulative prednisolone dose (even after an adjustment for age), or disease duration with bone microarchitecture. The duration of high-dose prednisolone (≥7.5 mg) was negatively associated with trabecular thickness (Tb.Th) at the distal radius. No differences in bone microarchitecture parameters between AIH, AIH/PBC, and PBC could be detected. In conclusion, AIH patients showed a severe age-dependent deterioration of the cortical bone microarchitecture, which is most likely the major contribution to the observed increased fracture risk in these patients. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4289DOI Listing
July 2021

[European Reference Network for Rare Hepatological Diseases (ERN RARE-LIVER)].

Internist (Berl) 2021 Apr 9;62(4):441-448. Epub 2021 Mar 9.

I. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland.

Patients with rare diseases often receive insufficient medical care. The European Reference Networks (ERNs) were initiated by the European Union to improve healthcare for patients with rare and complex diseases within Europe. The Reference Network on Hepatological Diseases (ERN RARE-LIVER), which consists of hepatological centres, scientific societies and numerous patient organizations, is one of 24 ERNs. The aim of ERN RARE-LIVER is high-quality healthcare for patients suffering from rare liver diseases, regardless of their place of residence. Standardization of treatment, coordination of research projects as well as training and teaching of patients, patient representatives and healthcare professionals are means to reach this goal. Virtual case discussions are offered via a web-based platform (Clinical Patient Management System), in which experts from the ERNs advise treating physicians on the diagnosis and therapy of rare diseases.
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http://dx.doi.org/10.1007/s00108-021-00986-2DOI Listing
April 2021

Clonal expansion and activation of tissue-resident memory-like Th17 cells expressing GM-CSF in the lungs of severe COVID-19 patients.

Sci Immunol 2021 02;6(56)

I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Germany.

Hyperinflammation contributes to lung injury and subsequent acute respiratory distress syndrome (ARDS) with high mortality in patients with severe coronavirus disease 2019 (COVID-19). To understand the underlying mechanisms involved in lung pathology, we investigated the role of the lung-specific immune response. We profiled immune cells in bronchoalveolar lavage fluid and blood collected from COVID-19 patients with severe disease and bacterial pneumonia patients not associated with viral infection. By tracking T cell clones across tissues, we identified clonally expanded tissue-resident memory-like Th17 cells (Trm17 cells) in the lungs even after viral clearance. These Trm17 cells were characterized by a a potentially pathogenic cytokine expression profile of and (GM-CSF). Interactome analysis suggests that Trm17 cells can interact with lung macrophages and cytotoxic CD8 T cells, which have been associated with disease severity and lung damage. High IL-17A and GM-CSF protein levels in the serum of COVID-19 patients were associated with a more severe clinical course. Collectively, our study suggests that pulmonary Trm17 cells are one potential orchestrator of the hyperinflammation in severe COVID-19.
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http://dx.doi.org/10.1126/sciimmunol.abf6692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128299PMC
February 2021

Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver.

JCI Insight 2021 Mar 22;6(6). Epub 2021 Mar 22.

Department of Medicine I.

The liver is an immune-privileged organ that can deactivate autoreactive T cells. Yet in autoimmune hepatitis (AIH), autoreactive T cells can defy hepatic control and attack the liver. To elucidate how tolerance to self-antigens is lost during AIH pathogenesis, we generated a spontaneous mouse model of AIH, based on recognition of an MHC class II-restricted model peptide in hepatocytes by autoreactive CD4+ T cells. We found that the hepatic peptide was not expressed in the thymus, leading to deficient thymic deletion and resulting in peripheral abundance of autoreactive CD4+ T cells. In the liver, autoreactive CD4+ effector T cells accumulated within portal ectopic lymphoid structures and maturated toward pathogenic IFN-γ and TNF coproducing cells. Expansion and pathogenic maturation of autoreactive effector T cells was enabled by a selective increase of plasticity and instability of autoantigen-specific Tregs but not of nonspecific Tregs. Indeed, antigen-specific Tregs were reduced in frequency and manifested increased IL-17 production, reduced epigenetic demethylation, and reduced expression of Foxp3. As a consequence, autoantigen-specific Tregs had a reduced suppressive capacity, as compared with that of nonspecific Tregs. In conclusion, loss of tolerance and the pathogenesis of AIH were enabled by combined failure of thymic deletion and peripheral regulation.
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http://dx.doi.org/10.1172/jci.insight.141462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026180PMC
March 2021

SARS-CoV-2 infection in patients with autoimmune hepatitis.

J Hepatol 2021 06 26;74(6):1335-1343. Epub 2021 Jan 26.

Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany. Electronic address:

Background & Aims: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) continues to have a devastating impact across the globe. However, little is known about the disease course in patients with autoimmune hepatitis (AIH).

Methods: Data for patients with AIH and SARS-CoV-2 infection were combined from 3 international reporting registries and outcomes were compared to those in patients with chronic liver disease of other aetiology (non-AIH CLD) and to patients without liver disease (non-CLD).

Results: Between 25 March and 24 October 2020, data were collected for 932 patients with CLD and SARS-CoV-2 infection including 70 with autoimmune hepatitis (AIH). Fifty-eight (83%) patients with AIH were taking ≥1 immunosuppressive drug. There were no differences in rates of major outcomes between patients with AIH and non-AIH CLD, including hospitalization (76% vs. 85%; p = 0.06), intensive care unit admission (29% vs. 23%; p = 0.240), and death (23% vs. 20%; p = 0.643). Factors associated with death within the AIH cohort included age (odds ratio [OR] 2.16/10 years; 1.07-3.81), and Child-Pugh class B (OR 42.48; 4.40-409.53), and C (OR 69.30; 2.83-1694.50) cirrhosis, but not use of immunosuppression. Propensity score matched (PSM) analysis comparing patients with AIH with non-AIH CLD demonstrated no increased risk of adverse outcomes including death (+3.2%; -9.2%-15.7%). PSM analysis of patients with AIH vs. non-CLD (n = 769) demonstrated increased risk of hospitalization with AIH (+18.4%; 5.6-31.2%), but equivalent risk of all other outcomes including death (+3.2%; -9.1%-15.6%).

Conclusion: Patients with AIH were not at increased risk of adverse outcomes despite immunosuppressive treatment compared to other causes of CLD and to matched cases without liver disease.

Lay Summary: Little is known about the outcomes of COVID-19 in patients with autoimmune hepatitis (AIH), a rare chronic inflammatory liver disease. This study combines data from 3 large registries to describe the course of COVID-19 in this patient group. We show that AIH patients do not appear to have an increased risk of death from COVID-19 compared to patients with other forms of liver disease and compared to patients without liver disease, despite the use of medications which suppress the immune system.
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http://dx.doi.org/10.1016/j.jhep.2021.01.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835076PMC
June 2021

Hepatitis E virus persists in the ejaculate of chronically infected men.

J Hepatol 2021 Jul 20;75(1):55-63. Epub 2021 Jan 20.

I. Department of Medicine, Gastroenterology and Hepatology, with the Sections Infectious Diseases and Tropical Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems and Heidelberg Partner sites, Germany.

Background & Aims: Hepatitis E virus (HEV) infections are prevalent worldwide. Various viruses have been detected in the ejaculate and can outlast the duration of viremia, indicating replication beyond the blood-testis barrier. HEV replication in diverse organs, however, is still widely misunderstood. We aimed to determine the occurrence, features and morphology of HEV in the ejaculate.

Methods: The presence of HEV in testis was assessed in 12 experimentally HEV-genotype 3-infected pigs. We further tested ejaculate, urine, stool and blood from 3 chronically HEV genotype 3-infected patients and 6 immunocompetent patients with acute HEV infection by HEV-PCR. Morphology and genomic characterization of HEV particles from various human compartments were determined by HEV-PCR, density gradient measurement, immune-electron microscopy and genomic sequencing.

Results: In 2 of the 3 chronically HEV-infected patients, we observed HEV-RNA (genotype 3c) in seminal plasma and semen with viral loads >2 logs higher than in the serum. Genomic sequencing showed significant differences between viral strains in the ejaculate compared to stool. Under ribavirin-treatment, HEV shedding in the ejaculate continued for >9 months following the end of viremia. Density gradient measurement and immune-electron microscopy characterized (enveloped) HEV particles in the ejaculate as intact.

Conclusions: The male reproductive system was shown to be a niche of HEV persistence in chronic HEV infection. Surprisingly, sequence analysis revealed distinct genetic HEV variants in the stool and serum, originating from the liver, compared to variants in the ejaculate originating from the male reproductive system. Enveloped HEV particles in the ejaculate did not morphologically differ from serum-derived HEV particles.

Lay Summary: Enveloped hepatitis E virus particles could be identified by PCR and electron microscopy in the ejaculate of immunosuppressed chronically infected patients, but not in immunocompetent experimentally infected pigs or in patients with acute self-limiting hepatitis E.
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http://dx.doi.org/10.1016/j.jhep.2020.12.030DOI Listing
July 2021

Lower Levels of Transaminases but Higher Levels of Serum Creatinine in Patients with Acute Hepatitis E in Comparison to Patients with Hepatitis A.

Pathogens 2021 Jan 12;10(1). Epub 2021 Jan 12.

Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

In patients with hepatitis E virus (HEV) infections, extrahepatic, particularly renal and hematological manifestations, are increasingly reported in the medical literature but have never been studied compared to a control cohort. We retrospectively analyzed medical records of consecutive patients that were diagnosed with acute hepatitis E (AHE) (n = 69) or acute hepatitis A (AHA) (n = 46) at the University Medical Center Hamburg Eppendorf from January 2009 to August 2019 for demographical, clinical, and laboratory information. Patients with AHE had significantly lower median levels of ALAT (798 U/L) and total bilirubin (1.8 mg/dL) compared to patients with AHA (2326 U/L; < 0.001 and 5.2 mg/dL; < 0.001), suggesting a generally less severe hepatitis. In contrast, patients with AHE had significantly higher median serum creatinine levels (0.9 mg/dL vs. 0.8 mg/dL; = 0.002) and lower median estimated glomerular filtration rate (eGFR) (91 mL/min/1.73 m vs. 109 mL/min/1.73 m; < 0.001) than patients with AHA. Leucocyte, neutrophil and lymphocyte count, hemoglobin, platelets, red cell distribution width (RDW), neutrophil to lymphocyte ratio (NLR), and RDW to lymphocyte ratio (RLR) did not differ between patients with AHE and those with AHA. Our observations indicate that renal but not hematological interference presents an underrecognized extrahepatic feature of AHE, while inflammation of the liver seems to be more severe in AHA.
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http://dx.doi.org/10.3390/pathogens10010060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826713PMC
January 2021

SARS-CoV-2 vaccination in patients with liver disease: responding to the next big question.

Lancet Gastroenterol Hepatol 2021 03 11;6(3):156-158. Epub 2021 Jan 11.

Oxford Liver Unit, Translational Gastroenterology Unit, University of Oxford, Oxford, UK. Electronic address:

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http://dx.doi.org/10.1016/S2468-1253(21)00008-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832019PMC
March 2021

Nanoparticle-mediated targeting of autoantigen peptide to cross-presenting liver sinusoidal endothelial cells protects from CD8 T-cell-driven autoimmune cholangitis.

Immunology 2021 Apr 7;162(4):452-463. Epub 2021 Jan 7.

Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

Autoimmune diseases are caused by adaptive immune responses to self-antigens. The development of antigen-specific therapies that suppress disease-related, but not unrelated immune responses in general, is an important goal of biomedical research. We have previously shown that delivery of myelin peptides to liver sinusoidal endothelial cells (LSECs) using LSEC-targeting nanoparticles provides effective protection from CD4 T-cell-driven autoimmune encephalomyelitis. Here, we investigated whether this methodology might also serve antigen-specific treatment of a CD8 T-cell-driven autoimmune disease. As a model for CD8 T-cell-mediated autoimmunity, we used OT-1 T-cell-driven cholangitis in K14-OVAp mice expressing the cognate MHC I-restricted SIINFEKL peptide in cholangiocytes. To study whether peptide delivery to LSECs could modulate cholangitis, SIINFEKL peptide-conjugated nanoparticles were administered intravenously one day before transfer of OT-1 T cells; five days after cell transfer, liver pathology and hepatic infiltrates were analysed. SIINFEKL peptide-conjugated nanoparticles were rapidly taken up by LSECs in vivo, which effectively cross-presented the delivered peptide on MHC I molecules. Intriguingly, K14-OVAp mice receiving SIINFEKL-loaded nanoparticles manifested significantly reduced liver damage compared with vehicle-treated K14-OVAp mice. Mechanistically, treatment with LSEC-targeting SIINFEKL-loaded nanoparticles significantly reduced the number of liver-infiltrating OT-1 T cells, which up-regulated expression of the co-inhibitory receptor PD-1 and down-regulated cytotoxic effector function and inflammatory cytokine production. These findings show that tolerogenic LSECs can effectively internalize circulating nanoparticles and cross-present nanoparticle-bound peptides on MHC I molecules. Therefore, nanoparticle-mediated autoantigen peptide delivery to LSECs might serve the antigen-specific treatment of CD8 T-cell-driven autoimmune disease.
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http://dx.doi.org/10.1111/imm.13298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968394PMC
April 2021

Seroprevalence of SARS-CoV-2 antibodies among hospital workers in a German tertiary care center: A sequential follow-up study.

Int J Hyg Environ Health 2021 03 30;232:113671. Epub 2020 Nov 30.

I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Germany.

We sequentially assessed the presence of SARS-CoV-2 IgG antibodies in 1253 hospital workers including 1026 HCWs at the University Medical Center Hamburg-Eppendorf at three time points during the early phase of the epidemic. By the end of the study in July 2020, the overall seroprevalence was 1.8% (n = 22), indicating the overall effectiveness of infection control interventions in mitigating coronavirus disease 2019 (COVID-19) in hospital workers.
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http://dx.doi.org/10.1016/j.ijheh.2020.113671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832715PMC
March 2021

Autoimmune hepatitis: from immunopathogenesis to diagnostic and therapeutic innovation.

Curr Opin Gastroenterol 2021 Mar;37(2):86-90

Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Purpose Of Review: To understand the pathogenesis of autoimmune hepatitis (AIH) and the accuracy of diagnosis and treatment options that have improved lately. We summarize the latest research.

Recent Findings: Concerning pathogenesis of AIH, different groups have identified pieces of the puzzle that fit together well: An altered microbiome in the gut results in a proinflammatory response in the liver. This response is built by type II natural killer cells and CD4 T cells with an inflammatory phenotype and marked tumor necrosis factor production. When looking specifically at autoantigenic CD4 T cells, these have a B-helper phenotype on transcriptomic analysis. This explains not only elevation of immunoglobulins in AIH, but also mechanistically the effect of anti-B-cell substances in treatment. Diagnosis is now facilitated by an improved diagnostic score for AIH also recognizing modern techniques for autoantibody detection. Treatment in the future will increasingly be focused on reducing dosage and duration of steroid exposition. In addition, B-cell-targeted treatments have been evaluated with considerable success.

Summary: Research in the past 18 months has improved the understanding of pathogenesis and thereby opened a number of possible treatment options. In addition, steroid use is cautioned by the recent findings.
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http://dx.doi.org/10.1097/MOG.0000000000000701DOI Listing
March 2021

Reply to: "Both tacrolimus and mycophenylate mophetil should be considered second-line therapy for autoimmune hepatitis".

J Hepatol 2021 Mar 9;74(3):755-756. Epub 2020 Dec 9.

Department of Clinical Science, University of Bergen, Bergen, Norway; Norwegian PSC Research Centre, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; European Reference Network on Hepatological Diseases (ERN RARE-LIVER).

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http://dx.doi.org/10.1016/j.jhep.2020.11.031DOI Listing
March 2021

Hepatocellular carcinoma: Intratumoral EpCAM-positive cancer stem cell heterogeneity identifies high-risk tumor subtype.

BMC Cancer 2020 Nov 23;20(1):1130. Epub 2020 Nov 23.

Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

Background: The translational interest in the intratumoral heterogeneity of hepatocellular carcinoma (HCC) has been increasing. The dismal prognosis of this pathology is linked to the features of the HCC harbouring cancer stem cells (CSC), represented by EpCAM-expression. However, the extent of the impact of intratumoral distribution of CSC-features, both on the recurrence after curative resection and on clinical outcome, remains unknown. To address this, we investigated the spatial heterogeneity of CSC-features with the aim of identifying the unique HCC patient subgroups amenable to adjuvant treatment.

Methods: We designed a tissue microarray (TMA) from patients who had received liver resection between 2011 and 2017. Tumor specimens were sampled at multiple locations (n = 3-8). EpCAM-positivity was assessed for intensity and proportion by applying a score dividing three groups: (i) negative (E-/-); (ii) heterogeneous (E-/+); and (iii) homogeneous (E+/+). The groups were further analysed with regard to time-to-recurrence (TTR) and recurrence-free-survival (RFS).

Results: We included 314 tumor spots from 69 patients (76.8% male, median age 66, liver cirrhosis/fibrosis 75.8%). The risk factors were alcohol abuse (26.2%), NASH (13.1%), HBV (15.5%), HCV (17.9%) and others (27.4%), representative of a typical Western cohort. E+/+ patients experienced significantly shorter TTR and RFS compared to E+/- and E-/- patients (TTR 5 vs. 19 months, p = 0.022; RFS 5 vs. 14 vs. 21 months, p = 0.016). Only homogeneous EpCAM-positivity correlated with higher AFP levels (> 400 ng/ml, p = 0.031).

Conclusions: Spatial heterogeneity of EpCAM-expression was markedly present in the cohort. Of note, only homogeneous EpCAM-expression correlated significantly with early recurrence, whereas heterogeneous EpCAM-expression was associated with clinical endpoints comparable to EpCAM-negativity. We identified a unique HCC subtype associated with a high risk of tumor recurrence.
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http://dx.doi.org/10.1186/s12885-020-07580-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682021PMC
November 2020

Monocytes as Potential Mediators of Pathogen-Induced T-Helper 17 Differentiation in Patients With Primary Sclerosing Cholangitis (PSC).

Hepatology 2020 10 8;72(4):1310-1326. Epub 2020 Oct 8.

1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background And Aims: T cells from patients with primary sclerosing cholangitis (PSC) show a prominent interleukin (IL)-17 response upon stimulation with bacteria or fungi, yet the reasons for this dominant T-helper 17 (Th17) response in PSC are not clear. Here, we analyzed the potential role of monocytes in microbial recognition and in skewing the T-cell response toward Th17.

Approach And Results: Monocytes and T cells from blood and livers of PSC patients and controls were analyzed ex vivo and in vitro using transwell experiments with cholangiocytes. Cytokine production was measured using flow cytometry, enzyme-linked immunosorbent assay, RNA in situ hybridization, and quantitative real-time PCR. Genetic polymorphisms were obtained from ImmunoChip analysis. Following ex vivo stimulation with phorbol myristate acetate/ionomycin, PSC patients showed significantly increased numbers of IL-17A-producing peripheral blood CD4 T cells compared to PBC patients and healthy controls, indicating increased Th17 differentiation in vivo. Upon stimulation with microbes, monocytes from PSC patients produced significantly more IL-1β and IL-6, cytokines known to drive Th17 cell differentiation. Moreover, microbe-activated monocytes induced the secretion of Th17 and monocyte-recruiting chemokines chemokine (C-C motif) ligand (CCL)-20 and CCL-2 in human primary cholangiocytes. In livers of patients with PSC cirrhosis, CD14CD16 and CD14CD16 monocytes/macrophages were increased compared to alcoholic cirrhosis, and monocytes were found to be located around bile ducts.

Conclusions: PSC patients show increased Th17 differentiation already in vivo. Microbe-stimulated monocytes drive Th17 differentiation in vitro and induce cholangiocytes to produce chemokines mediating recruitment of Th17 cells and more monocytes into portal tracts. Taken together, these results point to a pathogenic role of monocytes in patients with PSC.
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http://dx.doi.org/10.1002/hep.31140DOI Listing
October 2020

Clinical and Radiological Characterization of Patients with Immobilizing and Progressive Stress Fractures in Methotrexate Osteopathy.

Calcif Tissue Int 2021 02 16;108(2):219-230. Epub 2020 Oct 16.

Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestraße 59, 22529, Hamburg, Germany.

Methotrexate (MTX) is one of the most commonly prescribed drugs for autoimmune rheumatic diseases. As there is no consensus on its negative effects on bone, the purpose of this investigation was to determine the clinical spectrum of patients with stress fractures due to long-term MTX treatment (i.e., MTX osteopathy). We have retrospectively analyzed data from 34 patients with MTX treatment, severe lower extremity pain and immobilization. MRI scans, bone turnover markers, bone mineral density (DXA) and bone microarchitecture (HR-pQCT) were evaluated. Stress fractures were also imaged with cone beam CT. While the time between clinical onset and diagnosis was prolonged (17.4 ± 8.6 months), the stress fractures had a pathognomonic appearance (i.e., band-/meander-shaped, along the growth plate) and were diagnosed in the distal tibia (53%), the calcaneus (53%), around the knee (62%) and at multiple sites (68%). Skeletal deterioration was expressed by osteoporosis (62%) along with dissociation of low bone formation and increased bone resorption. MTX treatment was discontinued in 27/34 patients, and a combined denosumab-teriparatide treatment initiated. Ten patients re-evaluated at follow-up (2.6 ± 1.5 years) had improved clinically in terms of successful remobilization. Taken together, our findings provide the first in-depth skeletal characterization of patients with pathognomonic stress fractures after long-term MTX treatment.
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http://dx.doi.org/10.1007/s00223-020-00765-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819927PMC
February 2021