Publications by authors named "Christoph Schramm"

219 Publications

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

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

Maternal Exercise Mediates Hepatic Metabolic Programming via Activation of AMPK-PGC1α Axis in the Offspring of Obese Mothers.

Cells 2021 May 19;10(5). Epub 2021 May 19.

Department of Pediatrics and Adolescent Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, D-50937 Cologne, Germany.

Maternal obesity is associated with an increased risk of hepatic metabolic dysfunction for both mother and offspring and targeted interventions to address this growing metabolic disease burden are urgently needed. This study investigates whether maternal exercise (ME) could reverse the detrimental effects of hepatic metabolic dysfunction in obese dams and their offspring while focusing on the AMP-activated protein kinase (AMPK), representing a key regulator of hepatic metabolism. In a mouse model of maternal western-style-diet (WSD)-induced obesity, we established an exercise intervention of voluntary wheel-running before and during pregnancy and analyzed its effects on hepatic energy metabolism during developmental organ programming. ME prevented WSD-induced hepatic steatosis in obese dams by alterations of key hepatic metabolic processes, including activation of hepatic ß-oxidation and inhibition of lipogenesis following increased AMPK and peroxisome-proliferator-activated-receptor-γ-coactivator-1α (PGC-1α)-signaling. Offspring of exercised dams exhibited a comparable hepatic metabolic signature to their mothers with increased AMPK-PGC1α-activity and beneficial changes in hepatic lipid metabolism and were protected from WSD-induced adipose tissue accumulation and hepatic steatosis in later life. In conclusion, this study demonstrates that ME provides a promising strategy to improve the metabolic health of both obese mothers and their offspring and highlights AMPK as a potential metabolic target for therapeutic interventions.
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http://dx.doi.org/10.3390/cells10051247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158724PMC
May 2021

Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis.

J Hepatol 2021 Apr 17. Epub 2021 Apr 17.

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.

Background & Aims: Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and progressive fibrosis of the biliary tree. The bile acid receptor TGR5 (GPBAR1) is found on biliary epithelial cells (BECs), where it promotes secretion, proliferation and tight junction integrity. Thus, we speculated that changes in TGR5-expression in BECs may contribute to PSC pathogenesis.

Methods: TGR5-expression and -localization were analyzed in PSC livers and liver tissue, isolated bile ducts and BECs from Abcb4, Abcb4/Tgr5 and ursodeoxycholic acid (UDCA)- or 24-norursodeoxycholic acid (norUDCA)-fed Abcb4 mice. The effects of IL8/IL8 homologues on TGR5 mRNA and protein levels were studied. BEC gene expression was analyzed by single-cell transcriptomics (scRNA-seq) from distinct mouse models.

Results: TGR5 mRNA expression and immunofluorescence staining intensity were reduced in BECs of PSC and Abcb4 livers, in Abcb4 extrahepatic bile ducts, but not in intrahepatic macrophages. No changes in TGR5 BEC fluorescence intensity were detected in liver tissue of other liver diseases, including primary biliary cholangitis. Incubation of BECs with IL8/IL8 homologues, but not with other cytokines, reduced TGR5 mRNA and protein levels. BECs from Abcb4 mice had lower levels of phosphorylated Erk and higher expression levels of Icam1, Vcam1 and Tgfβ2. Overexpression of Tgr5 abolished the activated inflammatory phenotype characteristic of Abcb4 BECs. NorUDCA-feeding restored TGR5-expression levels in BECs in Abcb4 livers.

Conclusions: Reduced TGR5 levels in BECs from patients with PSC and Abcb4 mice promote development of a reactive BEC phenotype, aggravate biliary injury and thus contribute to the pathogenesis of sclerosing cholangitis. Restoration of biliary TGR5-expression levels represents a previously unknown mechanism of action of norUDCA.

Lay Summary: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease-associated with progressive inflammation of the bile duct, leading to fibrosis and end-stage liver disease. Bile acid (BA) toxicity may contribute to the development and disease progression of PSC. TGR5 is a membrane-bound receptor for BAs, which is found on bile ducts and protects bile ducts from BA toxicity. In this study, we show that TGR5 levels were reduced in bile ducts from PSC livers and in bile ducts from a genetic mouse model of PSC. Our investigations indicate that lower levels of TGR5 in bile ducts may contribute to PSC development and progression. Furthermore, treatment with norUDCA, a drug currently being tested in a phase III trial for PSC, restored TGR5 levels in biliary epithelial cells.
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http://dx.doi.org/10.1016/j.jhep.2021.03.029DOI 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

Combination of fibrates with obeticholic acid is able to normalise biochemical liver tests in patients with difficult-to-treat primary biliary cholangitis.

Aliment Pharmacol Ther 2021 05 25;53(10):1138-1146. Epub 2021 Mar 25.

Paris, France.

Background: Obeticholic acid (OCA) and fibrates are second-line therapies for patients with primary biliary cholangitis (PBC) with an inadequate response to ursodeoxycholic acid (UDCA).

Aim: To know whether OCA and fibrates, administered together in combination with UDCA, have additive beneficial effects in patients with difficult-to-treat PBC.

Methods: PBC patients treated for ≥3 months with UDCA, OCA and fibrates (bezafibrate or fenofibrate) due to failure of either second-line therapy were included in a multicentre, uncontrolled retrospective cohort study. Changes in biochemical liver tests and pruritus were analysed using a generalised linear mixed-effect model.

Results: Among 58 patients included, half received OCA as second-line and fibrates as third-line therapy (Group OCA-Fibrate), while the other half had the inverse therapeutic sequence (Group Fibrate-OCA). The mean duration of triple therapy was 11 months (range 3-26). Compared to dual therapy, triple therapy was associated with a significant gain in alkaline phosphatase (ALP) reduction: 22% per first year (95% CI 12%-31%), an effect that was stronger in OCA-Fibrate than in Fibrate-OCA group. Triple therapy was associated with a 3.4 (95% CI 1.4-8.2) odds ratio (OR) of reaching normal ALP and with a significant decrease in gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin. The ORs of achieving the Paris-2 and Toronto criteria of adequate biochemical response were 6.8 (95% CI 2.8-16.7) and 9.2 (95% CI 3.4-25.1) respectively. Finally, triple therapy significantly improved pruritus in OCA-Fibrate but not in Fibrate-OCA group.

Conclusions: Triple therapy with UDCA, OCA and fibrates is able to normalise biochemical liver tests and improve pruritus in patients with difficult-to-treat PBC.
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http://dx.doi.org/10.1111/apt.16336DOI Listing
May 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

Environmental and Dietary Risk Factors for Colonic Diverticulosis and Diverticulitis.

J Gastrointestin Liver Dis 2021 Mar 13;30(1):66-72. Epub 2021 Mar 13.

Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.

Background And Aims: Colonic diverticulosis (CD) is among the most common conditions of the large bowel. Several factors have been associated with an increased risk of CD and its complications, including advanced age, obesity, physical inactivity, and a low-fiber diet. Available data is conflicting and a comprehensive analysis of different bowel, dietary and environmental habits linked with CD is lacking. We aimed to investigate the relationship between potential risk factors and CD prevalence using full data from a colonoscopy-based cross-sectional study in Europe.

Methods: The study was conducted at three tertiary referral centers in Germany and Lithuania. It included consecutive adult patients referred for routine colonoscopy who completed a detailed questionnaire on our considered multiple risk factors for diverticulosis and diverticulitis, including dietary and environmental factors, and bowel habits.

Results: The study included 1,333 patients, 696 women and 635 men. Colonic diverticulosis was diagnosed in 858 (64%) of patients. Multivariate analysis revealed that age (OR: 1.08, 95%CI: 1.06-1.10, p<0.001) and obesity (OR: 1.05, 95%CI: 1.02-1.09, p=0.004) were associated with CD. We also revealed new risk factors for CD: increased frequency of bowel movements (OR: 0.10, 95%CI: 0.03-0.33, p<0.001) and feeling of incomplete bowel emptying (OR: 2.05, 95%CI: 1.47-2.87, p<0.001). Older participants had reduced odds (OR: 0.921, 95 CI: 0.89-0.95, p<0.05) of diverticulitis compared to younger subjects. Feeling of incomplete bowel emptying after defecation was associated with increased odds (OR: 2.769, 95% CI 1.35-5.7, p<0.006) for diverticulitis. Moreover, participants with a higher educational status had increased odds (OR: 2.453, 95%CI: 1.31-4.59, p=0.005) for diverticulitis compared to the lower education group.

Conclusions:  Study shows that older age, obesity, frequency of bowel movements, and feeling of incomplete bowel emptying are associated with the risk of CD. Furthermore, older age, feeling of incomplete bowel emptying, and higher education were associated with the risk of diverticulitis among CD patients.
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http://dx.doi.org/10.15403/jgld-3208DOI Listing
March 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

Efficacy of a Brief, Peer-Delivered Self-management Intervention for Patients With Rare Chronic Diseases: A Randomized Clinical Trial.

JAMA Psychiatry 2021 Jun;78(6):607-615

Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Importance: Patients coping with rare diseases need psychosocial support.

Objective: To evaluate the efficacy of a brief, transdiagnostic, peer-delivered intervention for patients with rare diseases in addition to care as usual (CAU) compared with CAU only.

Design, Setting, And Participants: In this 2-group randomized clinical trial conducted from October 5, 2017, to July 12, 2019, patients were recruited via specialized clinics and patient organizations across Germany and participated from home. The study included consecutive adult patients with neurofibromatosis type 1, Marfan syndrome, primary sclerosing cholangitis, and pulmonary arterial hypertension who have limited functionality because of the disease. Exclusion criteria were a life-threatening health status and ongoing psychotherapeutic treatment. Of 143 patients screened for eligibility with a semistructured telephone interview, 54 were excluded, and 89 were randomized: 45 patients were randomly allocated to the peer-delivered intervention group, and 44 to the control group; 87 patients (98%) completed the 6-month follow-up assessment. The analysis was performed using an intention-to-treat principle. Data cleansing and analysis were conducted between April 25, 2019, and February 13, 2020.

Interventions: The 6-week intervention consisted of a self-help book and telephone-based peer counseling in addition to CAU. The control group received CAU alone. Peer counselors received training, structured consultation guidelines, and supervision.

Main Outcomes And Measures: The primary outcome was acceptance of the disease as assessed using the Illness Cognition Questionnaire (ICQ; mean sum scores range from 0 to 18, with higher values representing more acceptance) 6 months after the intervention. Secondary outcomes included self-reported coping strategies (Health Education Impact Questionnaire), illness cognition (ICQ and Illness Perception Questionnaire), depression severity (Patient Health Questionnaire 9-item depression scale), anxiety severity (Generalized Anxiety Disorder Scale), quality of life (12-Item Short-Form Health Survey), and social support (Social Support Questionnaire). Outcomes were assessed before the intervention, after the intervention, and at a 6-month follow-up.

Results: The mean (SD) age of the 89 participating patients was 46.3 (14.9) years; 59 (66%) were women. There were no group differences regarding baseline variables. All patients allocated to the intervention group completed the intervention. Six months after the intervention, but not directly after completing the program, the intervention group had significantly higher rates of acceptance (ICQ) of the disease (primary outcome) compared with the CAU group. Mean (SD) baseline ICQ scores were 9.61 (3.79) in the control group and 9.86 (3.40) in the intervention group. Mean (SE) ICQ scores at 6 months were 10.32 (0.42) for the control group and 11.79 (0.42) for the intervention group, with a significant mean difference of -1.47 (95% CI, -2.63 to -0.31; P = .01). Several secondary outcomes, including different coping strategies, social support, and mental quality of life, were significantly higher after the intervention compared with the control group.

Conclusions And Relevance: In this randomized clinical trial, a self-help and peer counseling intervention improved patients' acceptance of their rare chronic diseases. Self-management and peer support can efficiently address the unique care needs of patients with rare diseases.

Trial Registration: isrctn.org Identifier: ISRCTN13738704.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.4783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905693PMC
June 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

Altered Gut Microbial Metabolism of Essential Nutrients in Primary Sclerosing Cholangitis.

Gastroenterology 2021 Apr 31;160(5):1784-1798.e0. Epub 2020 Dec 31.

Norwegian Primary Sclerosing Cholangitis Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway. Electronic address:

Background & Aims: To influence host and disease phenotype, compositional microbiome changes, which have been demonstrated in patients with primary sclerosing cholangitis (PSC), must be accompanied by functional changes. We therefore aimed to characterize the genetic potential of the gut microbiome in patients with PSC compared with healthy controls (HCs) and patients with inflammatory bowel disease (IBD).

Methods: Fecal DNA from 2 cohorts (1 Norwegian and 1 German), in total comprising 136 patients with PSC (58% with IBD), 158 HCs, and 93 patients with IBD without PSC, were subjected to metagenomic shotgun sequencing, generating 17 billion paired-end sequences, which were processed using HUMAnN2 and MetaPhlAn2, and analyzed using generalized linear models and random effects meta-analyses.

Results: Patients with PSC had fewer microbial genes compared with HCs (P < .0001). Compared with HCs, patients with PSC showed enrichment and increased prevalence of Clostridium species and a depletion of, for example, Eubacterium spp and Ruminococcus obeum. Patients with PSC showed marked differences in the abundance of genes related to vitamin B6 synthesis and branched-chain amino acid synthesis (Q < .05). Targeted metabolomics of plasma from an independent set of patients with PSC and controls found reduced concentrations of vitamin B6 and branched-chain amino acids in PSC (P < .0001), which strongly associated with reduced liver transplantation-free survival (log-rank P < .001). No taxonomic or functional differences were detected between patients with PSC with and without IBD.

Conclusions: The gut microbiome in patients with PSC exhibits large functional differences compared with that in HCs, including microbial metabolism of essential nutrients. Alterations in related circulating metabolites associated with disease course, suggesting that microbial functions may be relevant for the disease process in PSC.
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http://dx.doi.org/10.1053/j.gastro.2020.12.058DOI Listing
April 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

Spontaneous cholecystocutaneous fistula: an uncommon complication of acute cholecystitis.

BMJ Case Rep 2020 Dec 15;13(12). Epub 2020 Dec 15.

Department of Gastroenterology and Hepatology, Faculty of Medicine and University Hospital Cologne, Cologne, North Rhine Westphalia, Germany.

A 78-year-old man presented to the hospital with acute right upper quadrant pain, fever and nausea. A focused abdominal ultrasound and abdominal CT scan were performed demonstrating an acute calculous cholecystitis with gallbladder perforation. Although a CT-guided cholecystostomy was performed and a pericholecystic abscess was relieved promptly, the patient developed a cholecystocutaneous fistula in the right hypochondriac region. A cholecystocutaneous fistula is an extremely rare complication that may occur in patients with acute calculous or acalculous cholecystitis, chronic gallstone disease, gallbladder carcinoma or prior hepatobiliary surgery.
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http://dx.doi.org/10.1136/bcr-2020-238063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745323PMC
December 2020

IL-17A/F enable cholangiocytes to restrict T cell-driven experimental cholangitis by upregulating PD-L1 expression.

J Hepatol 2021 Apr 13;74(4):919-930. Epub 2020 Nov 13.

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

Background & Aims: IL-17A-producing T cells are present in autoimmune cholestatic liver diseases; however, little is known about the contribution of IL-17 to periductal immune responses. Herein, we investigated the role of IL-17 produced by antigen-specific CD8 T cells in a mouse model of cholangitis and in vitro in human cholangiocyte organoids.

Methods: K14-OVAp mice express a major histocompatibility complex I-restricted ovalbumin (OVA) peptide sequence (SIINFEKL) on cholangiocytes. Cholangitis was induced by the adoptive transfer of transgenic OVA-specific ovalbumin transgene (OT)-1 CD8 T cells that either had OT-1 or lacked IL-17A/F (OT-1). The response of mouse and human cholangiocytes/organoids to IL-17A was assessed in vitro.

Results: Transfer of OVA-specific OT-1 cells significantly aggravated periductal inflammation in K14-OVAp recipient mice compared with transfer of OT-1 T cells. OT-1 T cells were highly activated in the liver and displayed increased cytotoxicity and proliferation. IL-17A/F produced by transferred OT-1 CD8 T cells induced upregulation of the inhibitory molecule programmed cell death ligand 1 (PD-L1) on cholangiocytes, restricting cholangitis by limiting cytotoxicity and proliferation of transferred cells. In contrast, OT-1 T cells failed to induce PD-L1 on cholangiocytes, resulting in uncontrolled expansion of cytotoxic CD8 T cells and aggravated cholangitis. Blockade of PD-L1 after transfer of OT-1 T cells with anti-PD-L1 antibody also resulted in aggravated cholangitis. Using human cholangiocyte organoids, we were able to confirm that IL-17A induces PD-L1 expression in cholangiocytes.

Conclusions: We demonstrate that by upregulating PD-L1 on cholangiocytes, IL-17 has an important role in restricting cholangitis and protecting against CD8 T cell-mediated inflammatory bile duct injury. Caution should be exercised when targeting IL-17 for the treatment of cholangitis.

Lay Summary: IL-17 is assumed to be a driver of inflammation in several autoimmune diseases, such as psoriasis. IL-17 is also present in inflammatory diseases of the bile duct, but its role in these conditions is not clear, as the effects of IL-17 depend on the context of its expression. Herein, we investigated the role of IL-17 in an experimental autoimmune cholangitis mouse model, and we identified an important protective effect of IL-17 on cholangiocytes, enabling them to downregulate bile duct inflammation via checkpoint inhibitor PD-L1.
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http://dx.doi.org/10.1016/j.jhep.2020.10.035DOI Listing
April 2021

Anti-glycoprotein 2 (anti-GP2) IgA and anti-neutrophil cytoplasmic antibodies to serine proteinase 3 (PR3-ANCA): antibodies to predict severe disease, poor survival and cholangiocarcinoma in primary sclerosing cholangitis.

Aliment Pharmacol Ther 2021 01 7;53(2):302-313. Epub 2020 Nov 7.

Szczecin, Poland.

Background: Primary sclerosing cholangitis (PSC) is associated with progressive liver disease and cholangiocarcinoma. Although risk stratification is crucial for making clinical decisions, it is hindered by a scarcity of proven prognostic markers.

Aims: To assess the value of novel anti-glycoprotein 2 (anti-GP2) and anti-neutrophil cytoplasmic antibodies to serine proteinase 3 (PR3-ANCA) in combination with PSC-specific clinical and laboratory markers as predictors of quality of life, disease severity, and cholangiocarcinoma in two large, independent cohorts of PSC patients METHODS: Discovery (338 Polish patients) and validation (178 German patients) cohorts with PSC were evaluated. Anti-GP2 (isoforms 1/4) was detected by ELISAs and PR3-ANCA by chemiluminescence immunoassay. Clinical and laboratory data were collected and analysed. The outcome was defined as liver transplantation-free survival and occurrence of cholangiocarcinoma during follow-up.

Results: In the discovery group, anti-GP2 IgA and PR3-ANCA were associated with liver dysfunction, anti-GP2 IgA with risk scores for PSC and anti-GP2 IgA with cirrhosis. All cholangiocarcinoma patients were positive for PR3-ANCA and/or anti-GP2 IgA. The association between anti-GP2 IgA and liver biochemistry, risk scores, cirrhosis, impaired survival, and cholangiocarcinoma was confirmed in the validation cohort. Cox proportional-hazards regression indicated anti-GP2 IgA as an independent variable of poor outcome in both study cohorts. Analysis of the combined data showed that anti-GP2 IgA and PR3-ANCA were independent predictors for cholangiocarcinoma, while anti-GP2 IgA and PR3-ANCA were indicators for poor survival.

Conclusions: Anti-GP2 and PR3-ANCA are prognostic antibodies in PSC as they identify patients at risk of severe disease, poor survival and biliary cancer.
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http://dx.doi.org/10.1111/apt.16153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821312PMC
January 2021

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

CK-18 cell death markers improve the prediction of histological remission in autoimmune hepatitis during biochemical remission.

Liver Int 2021 01;41(1):123-127

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Incomplete histological remission of autoimmune hepatitis (AIH) is associated with a reduced long-term survival and an increased relapse rate even during biochemical remission (BR). The aim of this international multicentre study was to explore the diagnostic fidelity of cytokeratin-18 cell death markers to noninvasively detect incomplete histological remission. Thereby, cytokeratin-18 cell death marker M65 but not ALT and immunoglobulins was significantly higher in patients with incomplete histological remission (mHAI ≥ 4) compared to those with mHAI ≤ 3. M65 levels > 305 U/L, identified in the training cohort, facilitated the noninvasive detection of incomplete histological remission with a sensitivity of 75% and negative predictive value of 86% in the validation cohort. While BR with M65 < 305 U/L suggested complete histological remission (86%), BR with M65 > 305 U/L reduced the rate of histological remission to 60%. In conclusion, M65 may help to better select patients for or to reduce surveillance liver biopsies in the future.
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http://dx.doi.org/10.1111/liv.14699DOI Listing
January 2021

Cell-autonomous hepatocyte-specific GP130 signaling is sufficient to trigger a robust innate immune response in mice.

J Hepatol 2021 Feb 25;74(2):407-418. Epub 2020 Sep 25.

Institute of Biochemistry, Christian-Albrechts-University Kiel, Germany. Electronic address:

Background & Aims: Interleukin (IL)-6 cytokine family members contribute to inflammatory and regenerative processes. Engagement of the signaling receptor subunit gp130 is common to almost all members of the family. In the liver, all major cell types respond to IL-6-type cytokines, making it difficult to delineate cell type-specific effects. We therefore generated mouse models for liver cell type-specific analysis of IL-6 signaling.

Methods: We produced mice with a Cre-inducible expression cassette encoding a designed pre-dimerized constitutive active gp130 variant. We bred these mice to different Cre-drivers to induce transgenic gp130 signaling in distinct liver cell types: hepatic stellate cells, cholangiocytes/liver progenitor cells or hepatocytes. We phenotyped these mice using multi-omics approaches, immunophenotyping and a bacterial infection model.

Results: Hepatocyte-specific gp130 activation led to the upregulation of innate immune system components, including acute-phase proteins. Consequently, we observed peripheral mobilization and recruitment of myeloid cells to the liver. Hepatic myeloid cells, including liver-resident Kupffer cells were instructed to adopt a bactericidal phenotype which ultimately conferred enhanced resistance to bacterial infection in these mice. We demonstrate that persistent hepatocyte-specific gp130 activation resulted in amyloid A amyloidosis in aged mice. In contrast, we did not observe overt effects of hepatic stellate cell- or cholangiocyte/liver progenitor cell-specific transgenic gp130 signaling.

Conclusions: Hepatocyte-specific gp130 activation alone is sufficient to trigger a robust innate immune response in the absence of NF-κB activation. We therefore conclude that gp130 engagement, e.g. by IL-6 trans-signaling, represents a safe-guard mechanism in innate immunity.

Lay Summary: Members of the interleukin-6 cytokine family signal via the receptor subunit gp130 and are involved in multiple processes in the liver. However, as several liver cell types respond to interleukin-6 family cytokines, it is difficult to delineate cell type-specific effects. Using a novel mouse model, we provide evidence that hepatocyte-specific gp130 activation is sufficient to trigger a robust systemic innate immune response.
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http://dx.doi.org/10.1016/j.jhep.2020.09.021DOI Listing
February 2021

Maternal exercise conveys protection against NAFLD in the offspring via hepatic metabolic programming.

Sci Rep 2020 09 22;10(1):15424. Epub 2020 Sep 22.

Department of Pediatrics and Adolescent Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Robert-Koch Str. 16, Building 44a, 50931, Cologne, Germany.

Maternal exercise (ME) during pregnancy has been shown to improve metabolic health in offspring and confers protection against the development of non-alcoholic fatty liver disease (NAFLD). However, its underlying mechanism are still poorly understood, and it remains unclear whether protective effects on hepatic metabolism are already seen in the offspring early life. This study aimed at determining the effects of ME during pregnancy on offspring body composition and development of NAFLD while focusing on proteomic-based analysis of the hepatic energy metabolism during developmental organ programming in early life. Under an obesogenic high-fat diet (HFD), male offspring of exercised C57BL/6J-mouse dams were protected from body weight gain and NAFLD in adulthood (postnatal day (P) 112). This was associated with a significant activation of hepatic AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor alpha (PPARα) and PPAR coactivator-1 alpha (PGC1α) signaling with reduced hepatic lipogenesis and increased hepatic β-oxidation at organ programming peak in early life (P21). Concomitant proteomic analysis revealed a characteristic hepatic expression pattern in offspring as a result of ME with the most prominent impact on Cholesterol 7 alpha-hydroxylase (CYP7A1). Thus, ME may offer protection against offspring HFD-induced NAFLD by shaping hepatic proteomics signature and metabolism in early life. The results highlight the potential of exercise during pregnancy for preventing the early origins of NAFLD.
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http://dx.doi.org/10.1038/s41598-020-72022-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508970PMC
September 2020

Aryl Hydrocarbon Receptor Activity in Hepatocytes Sensitizes to Hyperacute Acetaminophen-Induced Hepatotoxicity in Mice.

Cell Mol Gastroenterol Hepatol 2021 12;11(2):371-388. Epub 2020 Sep 12.

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

Background & Aims: Acetaminophen (APAP)-induced liver injury is one of the most common causes of acute liver failure, however, a clear definition of sensitizing risk factors is lacking. Here, we investigated the role of the ligand-activated transcription factor aryl hydrocarbon receptor (Ahr) in APAP-induced liver injury. We hypothesized that Ahr, which integrates environmental, dietary, microbial and metabolic signals into complex cellular transcriptional programs, might act as a rheostat for APAP-toxicity.

Methods: Wildtype or conditional Ahr knockout mice lacking Ahr in hepatocytes (Alb) or myeloid cells (LysM) were treated with the specific Ahr ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) together with APAP.

Results: Ahr activation by ITE, which by itself was non-toxic, exacerbated APAP-induced hepatotoxicity compared to vehicle-treated controls, causing 80% vs. 0% mortality after administration of a normally sublethal APAP overdose. Of note, Ahr activation induced hepatocyte death even at APAP doses within the therapeutic range. Aggravated liver injury was associated with significant neutrophil infiltration; however, lack of Ahr in myeloid cells did not protect LysM mice from exacerbated APAP hepatotoxicity. In contrast, Alb mice were largely protected from ITE-induced aggravated liver damage, indicating that Ahr activation in hepatocytes, but not in myeloid cells, was instrumental for disease exacerbation. Mechanistically, Ahr activation fueled hepatic accumulation of toxic APAP metabolites by up-regulating expression of the APAP-metabolizing enzyme Cyp1a2, a direct Ahr downstream target.

Conclusions: Ahr activation in hepatocytes potentiates APAP-induced hepatotoxicity. Thus, individual exposition to environmental Ahr ligands might explain individual sensitivity to hyperacute liver failure.
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http://dx.doi.org/10.1016/j.jcmgh.2020.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779786PMC
September 2020

Risk factors associated with bleeding after prophylactic endoscopic variceal ligation in cirrhosis.

Endoscopy 2021 Mar 7;53(3):226-234. Epub 2020 Sep 7.

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

Background: Prophylactic endoscopic variceal band ligation (EVL) is frequently performed in patients with liver cirrhosis. The aim of our study was to identify factors associated with early upper gastrointestinal bleeding (UGIB) in cirrhosis patients after prophylactic EVL.

Methods: 787 nonemergency EVLs performed in 444 patients in two German University medical centers were analyzed retrospectively.

Results: Within 30 days after EVL, 38 UGIBs were observed (4.8 % of all procedures). Bilirubin levels (hazard ratio [HR] 1.5, 95 % confidence interval [CI] 1.2-2.0 for a 2-fold increase) and presence of varices grade III/IV according to Paquet (HR 2.6, 95 %CI 1.3-5.0 compared with absence or smaller sized varices) were independently associated with UGIB following EVL. International normalized ratio (INR) was associated with bleeding events in the univariate analysis but did not reach statistical significance after adjustment for bilirubin and presence of varices grade III/IV (HR 1.2, 95 %CI 0.9-1.6 for an increase by 0.25). There was no statistically significant association between platelet count or fibrinogen levels and UGIB. Substitution of coagulation products did not affect incidence of bleeding after EVL, which also applied to patients with "coagulopathy" (INR > 1.5 and/or platelet count < 50 × 10/L). No association between proton pump inhibitor therapy and post-EVL UGIB was observed.

Conclusions: EVL is a safe procedure and immediate bleeding complications are rare. Serum bilirubin levels and size of varices, rather than coagulation indices, are associated with UGIB after EVL. Our data do not support the preventive substitution of blood or coagulation products.
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http://dx.doi.org/10.1055/a-1214-5355DOI Listing
March 2021

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

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

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

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

The Effects of Androgens on T Cells: Clues to Female Predominance in Autoimmune Liver Diseases?

Front Immunol 2020 29;11:1567. Epub 2020 Jul 29.

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

The immune system responds differently in women and in men. Generally speaking, adult females show stronger innate and adaptive immune responses than males. This results in lower risk of developing most of the infectious diseases and a better ability to clear viral infection in women (1-5). On the other hand, women are at increased risk of developing autoimmune diseases (AID) such as rheumatoid arthritis, multiple sclerosis (MS), systemic lupus erythematosus (SLE), Sjögren's syndrome, and the autoimmune liver diseases autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) (6). Factors contributing to the female sex bias in autoimmune diseases include environmental exposure, e.g., microbiome, behavior, and genetics including X chromosomal inactivation of genes. Several lines of evidence and clinical observations clearly indicate that sex hormones contribute significantly to disease pathogenesis, and the role of estrogen in autoimmune diseases has been extensively studied. In many of these diseases, including the autoimmune liver diseases, T cells are thought to play an important pathogenetic role. We will use this mini-review to focus on the effects of androgens on T cells and how the two major androgens, testosterone and dihydrotestosterone, potentially contribute to the pathogenesis of autoimmune liver diseases (AILD).
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http://dx.doi.org/10.3389/fimmu.2020.01567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403493PMC
April 2021

Automatic detection of venous air embolism using transesophageal echocardiography in patients undergoing neurological surgery in the semi-sitting position: a pilot study.

J Clin Monit Comput 2020 Aug 18. Epub 2020 Aug 18.

Department of Anesthesiology, Medical Faculty, University of Heidelberg, Im Neuenheimer Feld 110, Heidelberg, 69120, Germany.

Neurological surgery in the semi-sitting position is linked with a pronounced incidence of venous air embolism (VAE) which can be fatal and therefore requires continuous monitoring. Transesophageal echocardiography (TEE) provides a high sensitivity for the intraoperative detection of VAE; however, continuous monitoring with TEE requires constant vigilance by the anaesthesiologist, which cannot be ensured during the entire surgical procedure. We implemented a fully automatic VAE detection system for TEE based on a statistical model of the TEE images. In the sequence of images, the cyclic heart activity is regarded as a quasi-periodic process, and air bubbles are detected as statistical outliers. The VAE detection system was evaluated by means of receiver operating characteristic (ROC) curves using a data set consisting of 155.14 h of intraoperatively recorded TEE video and a manual classification of periods with visible VAE. Our automatic detection system accomplished an area under the curve (AUC) of 0.945 if all frames with visible VAE were considered as detection target, and an AUC of 0.990 if frames with the least severe optical grade of VAE were excluded from the analysis. Offline-review of the recorded TEE videos showed that short embolic events (≤ 2 min) may be overseen when monitoring TEE video manually. Automatic detection of VAE is feasible and could provide significant support to anaesthesiologists in clinical practice. Our proposed algorithm might possibly even offer a higher sensitivity compared to manual detection. The specificity, however, requires improvement to be acceptable for practical application. Trial Registration: German Clinical Trials Register (DRKS00011607).
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http://dx.doi.org/10.1007/s10877-020-00568-xDOI Listing
August 2020

Update of the simplified criteria for autoimmune hepatitis: Evaluation of the methodology for immunoserological testing.

J Hepatol 2021 Feb 27;74(2):312-320. Epub 2020 Jul 27.

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

Background & Aims: The simplified criteria for the diagnosis of autoimmune hepatitis (AIH) include immunofluorescence testing (IFT) of antinuclear and smooth muscle autoantibodies (ANA and SMA) on rodent tissue sections. We aimed to establish scoring criteria for the implementation of ANA IFT on human epithelioma-2 (HEp-2) cells and ELISA-based testing.

Methods: ANA and SMA reactivity of 61 AIH sera and 72 non-alcoholic fatty liver disease controls were separately assessed on tissue sections and HEp-2 cells to compare the diagnostic value at increasing titers. A total of 113 patients with AIH at diagnosis and 202 controls from 3 European centers were assessed by IFT as well as 3 different commercially available ANA ELISA and 1 anti-F-actin ELISA.

Results: ANA assessment by IFT on liver sections had 83.6% sensitivity and 69.4% specificity for AIH at a titer of 1:40. On HEp-2 cells, sensitivity and specificity were 75.4% and 73.6%, respectively, at an adjusted titer of 1:160. Area under the curve (AUC) values of ANA ELISA ranged from 0.70-0.87, with ELISA coated with HEp-2 extracts in addition to selected antigens performing significantly better. SMA assessment by IFT had the highest specificity for the SMA-VG/T pattern and anti-microfilament reactivity on HEp-2 cells. ELISA-based anti-F-actin evaluation was a strong predictor of AIH (AUC 0.88) and performed better than SMA assessment by IFT (AUC 0.77-0.87).

Conclusion: At adjusted cut-offs, both ANA IFT using HEp-2 cells and ELISA-based autoantibody evaluation for ANA and SMA are potential alternatives to tissue-based IFT for the diagnosis of AIH.

Lay Summary: Autoantibodies are a hallmark of autoimmune hepatitis and are traditionally tested for by immunofluorescence assays on rodent tissue sections. Herein, we demonstrate that human epithelioma cells can be used as a reliable substrate for immunofluorescence testing. ELISA-based testing is also a potentially reliable alternative for autoantibody assessment in autoimmune hepatitis. We propose the implementation of these testing methods into the simplified criteria for the diagnosis of autoimmune hepatitis.
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http://dx.doi.org/10.1016/j.jhep.2020.07.032DOI Listing
February 2021

Editorial: gut microbiota profile in patients with autoimmune hepatitis-a clue for adjunctive probiotic therapy? Authors' reply.

Aliment Pharmacol Ther 2020 07;52(2):394-395

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

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http://dx.doi.org/10.1111/apt.15819DOI Listing
July 2020

Detection rates for adenomas, serrated polyps and clinically relevant serrated polyps can be easily estimated by individually calculated detection rate ratios.

Scand J Gastroenterol 2020 Jun 11;55(6):745-751. Epub 2020 Jun 11.

Department of Gastroenterology and Hepatology, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

Adenoma detection rate (ADR) is a key quality indicator for colonoscopy; however, it is cumbersome to obtain. We investigated if detection rates (DRs) for adenomas, serrated polyps (SPs) and clinically relevant SP (crSPDR) can be accurately estimated by individualized DR ratios (DRRs) in a multicenter primary colonoscopy screening cohort of average-risk individuals. DRRs were calculated by dividing DRs for a certain polyp entity by polyp detection rate (PDR) for each endoscopist individually on the basis of his/her first 50 (DRR) and 100 (DRR) consecutive colonoscopies. DRs were estimated for each endoscopist by multiplying his/her DRR for a certain polyp entity with his/her PDR of subsequent colonoscopies in groups of 50 (DRR) and 100 (DRR) consecutive colonoscopies. Estimated and actual DRs were compared. Estimated DRs showed a strong correlation with actual DRs for adenomas ( = 0.86 and 0.87; each < .001), SPs ( = 0.85 and 0.91; each < .001) and crSPs ( = 0.82 and 0.86; each < .001) using DRRs derived from first 50 and 100 consecutive colonoscopies. Corresponding root mean square error (RMSE) between individual estimated and actual DRs using DRR and DRR was 5.3(±4.6)% and 4.5(±4.8)% for adenomas, 5.2(±4.1)% and 3.9(±2.8)% for SP, 3.1(±3.1)% and 2.8(±2.5)% for crSP, respectively. RMSE was not significantly different between DRR and DRR for ADR ( = .445), SPDR ( = .178) and crSP ( = .544). DR for all relevant polyp entities can be accurately estimated by using individual DRRs. This approach may enable endoscopists to easily track their performance measures in daily routine.
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http://dx.doi.org/10.1080/00365521.2020.1774643DOI Listing
June 2020