Publications by authors named "Hanno Ehlken"

29 Publications

  • Page 1 of 1

Laparoscopic lymph node sampling: a new concept for patients with high-risk early esophagogastric junction cancer resected endoscopically.

Gastrointest Endosc 2021 Feb 24. Epub 2021 Feb 24.

Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

Background And Aims: Endoscopic resection is considered as curative treatment for early upper GI cancers under certain histologic (low-risk) criteria. In tumors not completely fulfilling these criteria but resected R0 endoscopically, esophagectomy is still advised due to an increased risk of lymph node (LN) metastases. However, the benefit-risk ratio especially in elderly patients at higher risk for radical surgery can be debated. We now present the outcome of our case series of laparoscopic lymph node sampling (LLS) in patients with T1 esophagogastric junction tumors, which had been completely resected by endoscopy but did not fulfill the low-risk criteria (G1/2, m, L0, V0).

Methods: Retrospective review of all T1 cancer cases undergoing LLS with at least one high-risk parameter after endoscopic resection during an 8-year period. Repeated endoscopy with biopsy and abdominothoracic CT had been performed before. Cases were divided into 2 periods, before (n=8) and after (n=12) introduction of an extended LLS protocol (additional resection of the left gastric artery). In case of positive LN, patients underwent conventional oncologic surgery; if negative, follow-up was performed. Main outcome was the number of harvested LN by means of LLS and the percentage of positive LNs found.

Results: 20 patients with cardia (n=1) and distal esophageal/Barrett's cancer (n=19) were included. The LN rate using the extended LLS technique increased by 12 % (period 1: median 12 (range 5-19; 95% CI, 3.4-15.4) vs period 2: median 17.5 (range 12-40; 95% CI, 12.8-22.2; p=0.013). There were 2 adverse events, 1 inadvertent chest tube removal, and 1 postoperative pneumonia. In 15% of cases patients had positive lymph nodes and in 2 cases there was local recurrence at the endoscopic resection site, all necessitating surgery.

Conclusion: An extended technique of laparoscopic lymph node sampling appears to provide adequate LN numbers and is a safe approach with short hospital stay only. Only long-term follow-up of larger patient numbers will allow conclusions about miss rate as well as oncologic adequacy of this concept.
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http://dx.doi.org/10.1016/j.gie.2021.02.014DOI Listing
February 2021

Possible tumour cell reimplantation during curative endoscopic therapy of superficial Barrett's carcinoma.

Gut 2021 Jan 13. Epub 2021 Jan 13.

Department of Interdisciplinary Endoscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Background And Aims: Endoscopic resection has been established as curative therapy for superficial cancer arising from Barrett's oesophagus (BE); recurrences are very rare. Based on a case series with unusual and massive early recurrences, we analyse the issue of tumour cell reimplantation.

Methods: This hypothesis was developed on the basis of two out of seven patients treated by circumferential (n=6) or nearly circumferential (n=1) en bloc and R0 endoscopic resection of T1 neoplastic BE. Subsequently, a prospective histocytological analysis of endoscope channels and accessories was performed in 2 phases (cytohistological analysis; test for cell viability) in 22 different oesophageal carcinoma patients undergoing endoscopy. Finally, cultures from two oesophageal adenocarcinoma cell lines were incubated with different triamcinolone concentrations (0.625-10 mg/mL); cell growth was determined on a Multiwell plate reader.

Results: Cancer regrowth in the two suspicious cases (male, 78/71 years) occurred 7 and 1 months, respectively, after curative tumour resection. Subsequent surgery showed advanced tumours (T2) with lymph node metastases; one patient died. On cytohistological examinations of channels and accessories, suspicious/neoplastic cells were found in 4/10 superficial and in all 5 advanced cancers. Further analyses in seven further advanced adenocarcinoma cases showed viable cells in two channel washing specimens. Finally, cell culture experiments demonstrated enhanced tumour cell growth by triamcinolone after 24 hours compared with controls.

Conclusions: Tumour cell reimplanation from contaminated endoscopes and accessories is a possible cause of local recurrence after curative endoscopic therapy for superficial Barrett carcinoma; also, corticosteroid injection could have promoted tumour regrowth in these cases.
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http://dx.doi.org/10.1136/gutjnl-2020-322723DOI Listing
January 2021

Histologic and Clinical Effects of Different Topical Corticosteroids for Eosinophilic Esophagitis: Lessons from an Updated Meta-Analysis of Placebo-Controlled Randomized Trials.

Digestion 2020 Jul 1:1-9. Epub 2020 Jul 1.

Institute of Medical Biometry and Epidemiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

Background: Topical corticosteroids (TS) have become standard therapy for eosinophilic esophagitis (EoE). However, a variety of drug formulations have been used for which results of histological and clinical responses may be different. We aimed at determining the short-term histologic efficacy of TS for EoE based on randomized placebo-controlled trials and to review clinical response.

Methods: We searched MEDLINE, ISI Web of Science, and clinicaltrials.gov for randomized controlled trials (RCTs) on TS versus placebo for active EoE published until June 2019. Treatment effects were calculated as risk ratios (RRs) comparing histologic remission between groups.

Results: Nine RCTs (6 budesonide and 3 fluticasone) involving a total of 483 participants were included. A substantial overall effect of TS on acute histologic remission (RR 12.5, 95% confidence interval 6.0-25.9) was found despite varying definitions of histologic response. Indirect comparisons between drug and formulation types showed a trend for a better histologic efficacy of budesonide (RR 13.5 vs. 10.4 fluticasone) and for the orodispersible tablet (RR 46.2 vs. 11.5 suspension, and 10.4 nebulized formula/spray), but only based on small patient numbers. Scores used for clinical response assessment were different between studies, and short-term clinical results were less impressive: significant differences favoring TS were found in 4/9 RCTs (4/6 budesonide, 0/3 fluticasone).

Conclusions: TS are effective for short-term induction of histological remission in EoE with less impressive clinical response rates. The mode of drug delivery to the esophagus may be a relevant factor for the degree of histologic remission. Further trials should use uniform assessment criteria and long-term patient-centered outcomes.
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http://dx.doi.org/10.1159/000507571DOI Listing
July 2020

Waiting times for endotherapy of early malignancy: No problem?

Gastrointest Endosc 2020 08 15;92(2):424-426. Epub 2020 Apr 15.

Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

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http://dx.doi.org/10.1016/j.gie.2020.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158833PMC
August 2020

Features and outcome of AIH patients without elevation of IgG.

JHEP Rep 2020 Jun 29;2(3):100094. Epub 2020 Feb 29.

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

Background & Aims: High IgG levels are considered a hallmark of autoimmune hepatitis (AIH). A subgroup of patients with AIH has IgG within the normal range despite evidence of clinical disease activity. The clinical significance of this biomarker has not been explored.

Methods: In a European multicentre study we compared biochemical, clinical and histological features from patients with AIH and normal IgG-values at diagnosis to an age- and sex-matched control group of patients with typical AIH presenting with elevated IgG. Data were assessed at diagnosis, after 12 months of therapy and at last follow-up.

Results: Out of 1,318 patients with AIH, 130 (10%) had normal IgG at presentation. Histological and biochemical parameters at diagnosis, as well as treatment response, showed no difference between groups. Stable remission off treatment was achieved more commonly in the normal IgG group than in the typical AIH group (24 8%;  = 0.0012). Patients of the control group not only had higher IgG levels (29.5 ± 5.8 12.5 ± 3.2 g/L; <0.0001), but also a higher IgG/IgA ratio (9.3 ± 6.9 5.4 ± 2.4;  <0.0001) at diagnosis. The IgG/IgA ratio only declined in patients with typical AIH and was no longer different between groups after 12 months (6.3 ± 4.3 5.5 ± 2.2;  = 0.1), indicating a selective increase of IgG in typical AIH and its suppression by immunosuppression. Autoantibody titres were higher in the typical AIH group, but not when controlled for IgG levels.

Conclusions: Compared to AIH with typical biochemical features, patients with normal IgG levels at diagnosis (i) show similar biochemical, serological and histological features and comparable treatment response, (ii) appear to lack the selective elevation of serum IgG levels observed in typical active AIH disease, (iii) may represent a subgroup with a higher chance of successful drug withdrawal.

Lay Summary: A characteristic feature of autoimmune hepatitis (AIH) is an elevation of immunoglobulin G (IgG), which is therefore used as a major diagnostic criterion, as well as to monitor treatment response. Nevertheless, normal IgG does not preclude the diagnosis of AIH. Therefore, we herein assessed the features of patients with AIH and normal IgG in a large multicentre study. This study demonstrates that about 10% of all patients with AIH have normal IgG; these patients are indistinguishable from other patients with AIH with respect to biochemical markers, liver histology, disease severity and treatment response, but might represent a subgroup with a higher chance of remission after drug withdrawal.
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http://dx.doi.org/10.1016/j.jhepr.2020.100094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139106PMC
June 2020

[Diagnostics and Treatment of indeterminate Biliary Stenoses].

Dtsch Med Wochenschr 2020 03 2;145(5):306-312. Epub 2020 Mar 2.

Biliary stenoses represent a differential diagnostic challenge. Diagnostic methods to clarify the underlying dignity are often invasive, and provide high specificity beside insufficient sensitivity. In many cases, an accurate diagnosis is only possible over time, and therefore limits curative treatment options. This article provides an overview of the diagnostic challenges and treatment options for unclear biliary stenosis.
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http://dx.doi.org/10.1055/a-0944-8835DOI Listing
March 2020

Alterations of the bile microbiome in primary sclerosing cholangitis.

Gut 2020 04 26;69(4):665-672. Epub 2019 Jun 26.

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

Background: Patients with primary sclerosing cholangitis (PSC) display an altered colonic microbiome compared with healthy controls. However, little is known on the bile duct microbiome and its interplay with bile acid metabolism in PSC.

Methods: Patients with PSC (n=43) and controls without sclerosing cholangitis (n=22) requiring endoscopic retrograde cholangiography were included prospectively. Leading indications in controls were sporadic choledocholithiasis and papillary adenoma. A total of 260 biospecimens were collected from the oral cavity, duodenal fluid and mucosa and ductal bile. Microbiomes of the upper alimentary tract and ductal bile were profiled by sequencing the 16S-rRNA-encoding gene (V1-V2). Bile fluid bile acid composition was measured by high-performance liquid chromatography mass spectrometry and validated in an external cohort (n=20).

Results: The bile fluid harboured a diverse microbiome that was distinct from the oral cavity, the duodenal fluid and duodenal mucosa communities. The upper alimentary tract microbiome differed between PSC patients and controls. However, the strongest differences between PSC patients and controls were observed in the ductal bile fluid, including reduced biodiversity (Shannon entropy, p=0.0127) and increase of pathogen (FDR=4.18×10) in PSC. abundance in ductal bile was strongly correlated with concentration of the noxious secondary bile acid taurolithocholic acid (r=0.60, p=0.0021).

Conclusion: PSC is characterised by an altered microbiome of the upper alimentary tract and bile ducts. Biliary dysbiosis is linked with increased concentrations of the proinflammatory and potentially cancerogenic agent taurolithocholic acid.
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http://dx.doi.org/10.1136/gutjnl-2019-318416DOI Listing
April 2020

Rate of Spleen Length Progression Is a Marker of Outcome in Patients With Primary Sclerosing Cholangitis.

Clin Gastroenterol Hepatol 2019 11 4;17(12):2613-2615. Epub 2019 Jan 4.

Department of Interdisciplinary Endoscopy, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Patients with primary sclerosing cholangitis (PSC) tend to develop progressive liver fibrosis and end-stage liver disease within 10-20 years. The International PSC Study Group declared research on surrogate endpoints a high-priority task not least for ongoing clinical trials on novel treatment options. The spleen in patients with PSC often enlarges even before cirrhosis develops. Transient elastography (TE) has been investigated as a dynamic and prognostic marker in PSC. However, TE is not generally accessible, measures only a small part of the right liver, and is prone to errors in obese patients, and liver stiffness is related to postprandial status, liver inflammation, and biliary obstruction. We have recently demonstrated that single-point spleen length (SL) measurement has a prognostic performance similar to liver stiffness measured by TE. SL measurement is a fast, simple, and ubiquitously available method. However, absolute spleen size depends on body height and sex, and single-point measurement of SL cannot be used to assess the effects of therapeutic interventions. To overcome these issues, we assessed the intra-individual development of spleen size over time (delta spleen length: dSL = SL - SL) to evaluate its role as a novel surrogate marker, which accounts for the dynamic nature of PSC progression.
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http://dx.doi.org/10.1016/j.cgh.2018.12.033DOI Listing
November 2019

Risk of endoscopic biliary interventions in primary sclerosing cholangitis is similar between patients with and without cirrhosis.

PLoS One 2018 20;13(8):e0202686. Epub 2018 Aug 20.

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

Background: Endoscopic retrograde cholangiography (ERC) is a mainstay of therapy in patients with primary sclerosing cholangitis (PSC) and obstructive cholestasis. Patients with liver cirrhosis have an increased risk of surgical complications and are more susceptible to infections. Since PSC often progresses to cirrhosis, we aimed to assess whether ERC is associated with increased risk of complications in patients with PSC and cirrhosis.

Methods: Out of 383 patients with PSC, 208 patients received endoscopic treatment between 2009-2017. Seventy patients had cirrhosis when ERC was performed and 138 patients had no signs of cirrhosis. Overall, 663 ERC procedures were analysed, with 250 ERC in patients with cirrhosis and 413 ERC in patients without cirrhosis. Data were analysed retrospectively from a prospectively acquired database using repeated measures logistic regression.

Results: Overall, 40 procedure-related complications were documented in 663 ERC interventions (6%). The rate of complications was similar between patients with and without cirrhosis (4.4% vs. 7.0%). First-time ERC was associated with a higher risk of complications (17.5% vs. 4.9%). Biliary sphincterotomy, stent placement and female sex, but not presence of liver cirrhosis, were identified as risk factors for overall complications in multivariate analysis. Patients without cirrhosis showed a significant decline of ALP and bilirubin levels after the first two interventions. In contrast, in patients with cirrhosis, ALP and bilirubin levels did not significantly decline after ERC.

Conclusions: In patients with PSC, cirrhosis was not a risk factor for post-ERC complications. Therefore, cirrhosis should not preclude endoscopic intervention in patients with clear clinical indication.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202686PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6101401PMC
February 2019

Patients with primary biliary cholangitis and fatigue present with depressive symptoms and selected cognitive deficits, but with normal attention performance and brain structure.

PLoS One 2018 10;13(1):e0190005. Epub 2018 Jan 10.

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

Background: In primary biliary cholangitis (PBC) fatigue is a major clinical challenge of unknown etiology. By demonstrating that fatigue in PBC is associated with an impaired cognitive performance, previous studies have pointed out the possibility of brain abnormalities underlying fatigue in PBC. Whether structural brain changes are present in PBC patients with fatigue, however, is unclear. To evaluate the role of structural brain abnormalities in PBC patients severely affected from fatigue we, therefore, performed a case-control cerebral magnetic resonance imaging (cMRI) study and correlated changes of white and grey brain matter with the cognitive and attention performance.

Methods: 20 female patients with PBC and 20 female age-matched controls were examined in this study. The assessment of fatigue, psychological symptoms, cognitive and attention performance included clinical questionnaires, established cognition tests and a computerized test battery of attention performance. T1-weighted cMRI and diffusion tensor imaging (DTI) scans were acquired with a 3 Tesla scanner. Structural brain alterations were investigated with voxel-based morphometry (VBM) and DTI analyses. Results were correlated to the cognitive and attention performance.

Results: Compared to healthy controls, PBC patients had significantly higher levels of fatigue and associated psychological symptoms. Except for an impairment of verbal fluency, no cognitive or attention deficits were found in the PBC cohort. The VBM and DTI analyses revealed neither major structural brain abnormalities in the PBC cohort nor correlations with the cognitive and attention performance.

Conclusions: Despite the high burden of fatigue and selected cognitive deficits, the attention performance of PBC patients appears to be comparable to healthy people. As structural brain alterations do not seem to be present in PBC patients with fatigue, fatigue in PBC must be regarded as purely functional. Future studies should evaluate, whether functional brain changes underlie fatigue in PBC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190005PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761833PMC
February 2018

Usefulness of biochemical remission and transient elastography in monitoring disease course in autoimmune hepatitis.

J Hepatol 2018 04 24;68(4):754-763. Epub 2017 Nov 24.

University Medical Centre Hamburg-Eppendorf (UKE), 1st Department of Medicine, Hamburg, Germany.

Background & Aims: Liver fibrosis regression but also progression may occur in patients with autoimmune hepatitis (AIH) under treatment. There is a need for non-invasive surrogate markers for fibrosis development in AIH to better guide immunosuppressive treatment. The aims of the study were to assess the impact of complete biochemical remission defined as normalisation of aminotransferases and IgG on histological activity and fibrosis development, and the value of repeat transient elastography (TE) measurement for monitoring disease progression in AIH.

Methods: A total of 131 liver biopsies from 60 patients with AIH and more than 900 TE from 125 patients with AIH, 130 with primary biliary cholangitis (PBC) and 100 with primary sclerosing cholangitis (PSC), were evaluated. Time intervals between TE were at least 12 months. Patients with AIH were treated for at least six months at first TE.

Results: In contrast to PBC and PSC, a decrease of liver stiffness (LS) was observed in the whole group of patients with AIH (-6.2%/year; 95% CI -12.6% to -0.2%; p = 0.04). The largest decrease of LS was observed in patients with severe fibrosis at baseline (F4: -11.7%/year; 95% CI -19% to -3.5%; p = 0.006). Complete biochemical remission was strongly linked to regression of LS ("remission": -7.5%/year vs. "no remission": +1.7%/year, p <0.001). Similarly, complete biochemical remission predicted low histological disease activity and was the only independent predictor for histological fibrosis regression (relative risk3.66; 95% CI1.54-10.2; p = 0.001). Patients with F3/F4-fibrosis, who remained in biochemical remission showed a considerable decrease of fibrosis stage (3.7 ± 0.5 to 1.8 ± 1.7; p = 0.007) on histological follow-up.

Conclusions: This study demonstrates that complete biochemical remission is a reliable predictor of a good prognosis in AIH and leads to fibrosis regression that can be monitored by TE.

Lay Summary: Autoimmune hepatitis is an inflammatory disease of the liver, which often progresses to cirrhosis if left untreated or in the case of insufficient treatment response. Current guidelines have defined biochemical remission (normalisation of biochemical markers for liver inflammation) as a major goal in the treatment of AIH. However, data on the prognostic relevance of this definition are scarce. Herein, we demonstrate that the current definition of biochemical remission is a reliable surrogate for low disease activity on histological assessment and for a beneficial long-term disease course. In addition, we establish transient elastography, a non-invasive ultrasound-based method of measuring scarring of liver tissue, as a reliable tool to monitor disease course in AIH.
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http://dx.doi.org/10.1016/j.jhep.2017.11.020DOI Listing
April 2018

Risk of cholangiocarcinoma in patients with primary sclerosing cholangitis: diagnosis and surveillance.

Curr Opin Gastroenterol 2017 03;33(2):78-84

a1st Department of MedicinebDepartment of Interdisciplinary Endoscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Purpose Of Review: Primary sclerosing cholangitis (PSC) is associated with an increased risk of hepatobiliary and extrahepatic malignancy. Particularly the risk of cholangiocarcinoma (CCA) is greatly increased. To provide potentially curative treatments for affected patients an early diagnosis of CCA is crucial. We here review the current advances with respect to CCA diagnosis and surveillance and discuss a rational approach on how to perform surveillance of CCA in PSC patients.

Recent Findings: Given the shortcomings of the current modalities for the surveillance and diagnosis of CCA in PSC, recent studies have focused on novel biomarkers for CCA. These include serum biomarkers (e.g., circulating angiopoeitin-2, cytokeratin-19 fragments, and antiglycoprotein 2 IgA autoantibodies, microRNA) as well as proteomics obtained from urine and/or bile. Novel approaches that may enhance the diagnostic value of brush cytology in future include the optimization of fluorescence in situ hybridization probes and the assessment of genetic aberrations. In addition, studies on advanced techniques (e.g., single-operator cholangioscopy and probe-based confocal laser endomicroscopy) have shown promising results with respect to CCA detection.

Summary: Despite recent advances in the diagnosis of CCA in PSC, the detection of early-stage CCA remains difficult. A better understanding of CCA pathogenesis and large prospective studies on novel biomarkers and techniques are required to timely diagnose CCA in the future.
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http://dx.doi.org/10.1097/MOG.0000000000000335DOI Listing
March 2017

Efficacy and Limitations of Budesonide as a Second-Line Treatment for Patients With Autoimmune Hepatitis.

Clin Gastroenterol Hepatol 2018 02 23;16(2):260-267.e1. Epub 2017 Jan 23.

First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Background & Aims: Many patients with autoimmune hepatitis (AIH) develop steroid-specific side effects or require doses of steroids that are unacceptable for long-term treatment. We investigated the efficacy of budesonide as an alternative steroid for patients previously treated with prednisolone who developed side effects or were unable to reduce their dose of prednisolone below acceptable levels. We also report the effects of more than 12 months of budesonide treatment in a large cohort of patients with AIH.

Methods: We performed a retrospective analysis of data from 60 patients (51 female) with AIH who were treated initially with prednisolone (mean time, 47 mo) but then switched to budesonide, managed at a single center in Germany from 2001 through June 2016. Patients were evaluated after 6 months, 12 months, 24 months, 36 months, and at the last follow-up evaluation; response to treatment with budesonide was assessed based on normal serum levels of aminotransferases and IgG (biochemical response).

Results: Thirty patients were switched to budesonide therapy because of prednisolone-induced side effects and 30 patients switched because of prednisolone dependency. Overall, a biochemical response was detected in 55% of patients after 6 months of budesonide treatment, in 70% after 12 months, and in 67% after 24 months. At the last follow-up evaluation (mean time, 63 mo) 23 patients (38%) still were receiving budesonide treatment. Fifteen patients (25%) had switched back to prednisolone therapy because of insufficient response to budesonide or its side effects. Fifteen patients with osteopenia at the beginning of budesonide treatment were followed up and evaluated by dual-energy X-ray absorptiometry. After a median of 24 months of budesonide treatment, bone mineral density had improved in 6 patients, remained stable in 8 patients, and worsened in 1 patient.

Conclusions: We performed a retrospective analysis of patients with AIH that confirmed the therapeutic value of budesonide beyond 12 months of treatment in patients who are intolerant to or dependent on prednisolone. Although budesonide-induced side effects appear to be mild in real life, effectiveness was limited in a considerable proportion of patients; close monitoring is advised.
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http://dx.doi.org/10.1016/j.cgh.2016.12.040DOI Listing
February 2018

No Evidence That Azathioprine Increases Risk of Cholangiocarcinoma in Patients With Primary Sclerosing Cholangitis.

Clin Gastroenterol Hepatol 2016 12 10;14(12):1806-1812. Epub 2016 Aug 10.

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

Background & Aims: Patients with primary sclerosing cholangitis (PSC) are at increased risk for developing cholangiocarcinoma (CCA). Patients with PSC also can have inflammatory bowel diseases (IBDs) or features of autoimmune hepatitis (AIH), and therefore are treated with azathioprine. Azathioprine has been associated with an increased risk for malignancy, therefore we investigated whether azathioprine use affects the risk of CCA in persons with PSC.

Methods: We performed a retrospective study of well-defined patients with PSC using data collected from 3 large-volume, tertiary care centers in Germany and Norway. We analyzed data from 638 patients (70% men; 5900 patient-years of follow-up evaluation); 91 patients had received azathioprine therapy (considered to be effective at 90 days after first intake). Risk analysis was performed using the Cox proportional hazard model when risks competing with study end points were present.

Results: Of patients who received azathioprine treatment, 3.3% developed CCA, compared with 6.8% of patients without azathioprine treatment. However, azathioprine did not significantly affect the risk for CCA (hazard ratio, 0.96; 95% confidence interval, 0.29-3.13; P = .94). The only factor associated with an increased risk of CCA was age 35 years or older at PSC diagnosis (hazard ratio, 3.87; 95% confidence interval, 1.96-7.67; P < .01). Patient sex, concomitant IBD, or AIH did not affect the risk of CCA. Overall, the cumulative 10-year incidence of CCA was 4.6% and the cumulative 15-year incidence was 7.7%.

Conclusions: A retrospective analysis of patients with PSC treated at tertiary centers in Europe found no evidence that azathioprine significantly affects the risk of CCA. Azathioprine therefore should not be withheld from patients with PSC and concomitant IBD and/or AIH.
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http://dx.doi.org/10.1016/j.cgh.2016.07.032DOI Listing
December 2016

Validation of Transient Elastography and Comparison with Spleen Length Measurement for Staging of Fibrosis and Clinical Prognosis in Primary Sclerosing Cholangitis.

PLoS One 2016 10;11(10):e0164224. Epub 2016 Oct 10.

1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.

Background: Patients with primary sclerosing cholangitis (PSC) develop progressive liver fibrosis and end-stage liver disease. Non-invasive and widely available parameters are urgently needed to assess disease stage and the risk of clinical progression. Transient elastography (TE) has been reported to predict fibrosis stage and disease progression. However, these results have not been confirmed in an independent cohort and comparison of TE measurement to other non-invasive means is missing.

Methods: In a retrospective study we collected data from consecutive PSC patients receiving TE measurements from 2006 to 2014 (n = 139). Data from 62 patients who also underwent a liver biopsy were used to assess the performance of TE and spleen length (SL) measurement for the staging of liver fibrosis. Follow-up data from this cohort (n = 130, Hamburg) and another independent cohort (n = 80, Paris) was used to compare TE and SL as predictors of clinical outcome applying Harrel's C calculations.

Results: TE measurement had a very good performance for the diagnosis and exclusion of higher fibrosis stages (≥F3: AUROC 0.95) and an excellent performance for the diagnosis and exclusion of cirrhosis (F4 vs. < F4: AUROC 0.98). Single-point TE measurement had very similar predictive power for patient outcome as previously published. In a combined cohort of PSC patients (n = 210), SL measurements had a similar performance as TE for the prediction of patient outcome (5 x cross-validated Harrel's C 0.76 and 0.72 for SL and TE, respectively).

Conclusions: Baseline TE measurement has an excellent performance to diagnose higher fibrosis stages in PSC. Baseline measurements of SL and TE have similar usefulness as predictive markers for disease progression in patients with PSC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164224PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056739PMC
May 2017

Transient elastography in autoimmune hepatitis: Timing determines the impact of inflammation and fibrosis.

J Hepatol 2016 10 26;65(4):769-775. Epub 2016 May 26.

University Medical Centre Hamburg-Eppendorf (UKE), 1st Department of Medicine, Hamburg, Germany. Electronic address:

Background & Aims: There is an unmet need for the non-invasive monitoring of fibrosis progression in patients with autoimmune hepatitis (AIH). The aim of this study was to assess the diagnostic performance of transient elastography in patients with AIH and to investigate the impact of disease activity on its diagnostic accuracy.

Methods: Optimal cut-offs were defined in a prospective pilot study (n=34) and the diagnostic performance of transient elastography validated in an independent second cohort (n=60). To explore the impact of disease activity on liver stiffness, patients were stratified according to biochemical response and the time interval between start of immunosuppression and transient elastography.

Results: Liver stiffness strongly correlated with histological fibrosis stage (pilot study: ρ=0.611, p<0.001; validation cohort: ρ=0.777, p<0.0001). ROC curves defined an area under the receiver operating curve of 0.95 for diagnosing cirrhosis at the optimal cut-off of 16kPa. The performance of transient elastography was impaired when patients were analysed in whom transient elastography was performed within 3months from start of treatment. In this setting, liver stiffness correlated with histological grading (ρ=0.558, p=0.001), but not with staging. In contrast, using the cut-off of 16kPa, the accuracy for diagnosing cirrhosis was excellent in patients treated for 6months or longer (area under the receiver operating curve 1.0).

Conclusions: Liver inflammation has a major impact on liver stiffness in the first months of AIH treatment. However, transient elastography has an excellent diagnostic accuracy for separating severe from non-severe fibrosis after 6months of immunosuppressive treatment.

Lay Summary: Transient elastography is a special ultrasound scan, which assesses liver stiffness as a surrogate marker for liver fibrosis/scarring. Transient elastography has been shown to be a reliable non-invasive method to assess liver fibrosis in various chronic liver diseases, it takes less than 5min and has a high patient acceptance. The current study validated for the first time this technique in a large cohort of patients with autoimmune hepatitis (AIH) and demonstrates that it is a reliable tool to detect liver fibrosis in treated AIH. For the monitoring of potential disease progression under treatment, the validation of liver stiffness as non-invasive marker of liver fibrosis will greatly improve patient care in autoimmune hepatitis.
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http://dx.doi.org/10.1016/j.jhep.2016.05.023DOI Listing
October 2016

Opposing role of tumor necrosis factor receptor 1 signaling in T cell-mediated hepatitis and bacterial infection in mice.

Hepatology 2016 08 18;64(2):508-21. Epub 2016 Apr 18.

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

Unlabelled: Death receptor (DR) ligands such as tumor necrosis factor (TNF) have been identified as fundamental mediators of liver damage both in mouse models and in humans. While the essential site of function of DR signaling is conceivably the hepatocyte, a systematic analysis is missing. Using mice with conditional gene ablation, we analyzed the tissue-specific function of DR signaling in T cell-dependent (concanavalin A) and independent (lipopolysaccharide/galactosamine) hepatitis and in models of bacterial infection (Listeria monocytogenes, lipopolysaccharide). We report that lipopolysaccharide/galactosamine-induced liver injury depends on hepatocyte-intrinsic TNF receptor 1 (p55, TNFR1). In contrast, we show that T cell-induced hepatitis was independent of TNFR1 signaling in hepatocytes, T cells, or endothelial cells. Moreover, T cell-induced hepatitis was independent of hepatocyte-intrinsic Fas-associated protein with death domain, TNF-related apoptosis-inducing ligand receptor, or Fas signaling. Instead, concanavalin A-induced hepatitis was completely prevented in mice with myeloid-derived cell (MDC)-specific deletion of TNFR1. Significantly, however, mice lacking TNFR1 in MDCs succumbed to listeria infection, although they displayed similar sensitivity toward endotoxin-induced septic shock when compared to control mice. These results suggest that TNFR1 signaling in MDCs is a critical mediator of both the detrimental and the protective functions of TNF in T cell-induced hepatitis and bacterial infection, respectively.

Conclusion: The critical site of action of DRs is completely dependent on the nature of hepatitis; the data specify MDCs as the essential cell type of TNFR1 function in T cell-mediated hepatitis and in the response to listeria, thereby identifying the opposing role of MDC TNFR1 in autoimmunity and bacterial infection. (Hepatology 2016;64:508-521).
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http://dx.doi.org/10.1002/hep.28551DOI Listing
August 2016

NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis.

Cancer Cell 2015 11;28(5):582-598

Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931, Cologne, Germany. Electronic address:

IκB kinase/nuclear [corrected] factor κB (IKK/NF-κB) signaling exhibits important yet opposing functions in hepatocarcinogenesis. Mice lacking NEMO in liver parenchymal cells (LPC) spontaneously develop steatohepatitis and hepatocellular carcinoma (HCC) suggesting that NF-κB prevents liver disease and cancer. Here, we show that complete NF-κB inhibition by combined LPC-specific ablation of RelA, c-Rel, and RelB did not phenocopy NEMO deficiency, but constitutively active IKK2-mediated NF-κB activation prevented hepatocellular damage and HCC in NEMO(LPC-KO) mice. Knock-in expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) prevented hepatocyte apoptosis and HCC, while RIPK1 ablation induced TNFR1-associated death domain protein (TRADD)-dependent hepatocyte apoptosis and liver tumors in NEMO(LPC-KO) mice, revealing distinct kinase-dependent and scaffolding functions of RIPK1. Collectively, these results show that NEMO prevents hepatocarcinogenesis by inhibiting RIPK1 kinase activity-driven hepatocyte apoptosis through NF-κB-dependent and -independent functions.
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http://dx.doi.org/10.1016/j.ccell.2015.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644221PMC
November 2015

Acute and Chronic Inflammation of the Biliary System.

Viszeralmedizin 2015 Jun 15;31(3):200-3. Epub 2015 Jun 15.

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

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http://dx.doi.org/10.1159/000434663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569206PMC
June 2015

How Should Cancer Surveillance in Primary Sclerosing Cholangitis Be Performed?

Viszeralmedizin 2015 Jun 9;31(3):173-7. Epub 2015 Jun 9.

University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease affecting the intra- and extrahepatic bile duct system that can ultimately cause liver cirrhosis. Apart from the risk of progression to end-stage liver disease the prognosis of PSC is primarily determined by the risk to develop hepatobiliary or extrahepatic malignancies. A reasonable surveillance strategy for PSC patients must allow the detection of early cancer that will permit a potentially curative therapy.

Methods: Current guidelines on malignancy within the context of PSC as well as the primary literature were reviewed for this article.

Results: Here, we focus on a concise review of the three tumors most commonly associated with PSC: cholangiocellular carcinoma (CCA), gallbladder cancer, and colorectal carcinoma. For cancer surveillance in this patient group, endoscopy, cholangiography, cross-sectional imaging, and the use of serum tumor markers are principally available. Furthermore, for the diagnosis of CCA novel approaches were recently suggested to improve sensitivity and specificity to detect this malignancy.

Conclusion: We review different aspects of cancer surveillance in patients with PSC. Since prospective data on the surveillance of malignant tumors is unavailable, we discuss a rational approach on how to perform cancer surveillance in patients with PSC.
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http://dx.doi.org/10.1159/000431350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569209PMC
June 2015

Patient selection based on treatment duration and liver biochemistry increases success rates after treatment withdrawal in autoimmune hepatitis.

J Hepatol 2015 Mar 18;62(3):642-6. Epub 2014 Oct 18.

University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany. Electronic address:

Background & Aims: In autoimmune hepatitis (AIH), relapse rates as high as 90% have been reported after treatment withdrawal. We therefore investigated, whether longer duration of treatment and proper patient selection could increase the long-term success rates after treatment withdrawal.

Methods: Following our previously published experience, treatment withdrawal was considered when biochemical remission was maintained under immunosuppressive monotherapy for at least 2 years. Remission was defined as repeatedly normal serum aminotransferase levels as well as normal IgG levels.

Results: Out of 288 patients with well-defined AIH, 28 patients were included. Median duration of treatment was 48.5 months (range 35-179) and a sustained remission was observed for 45 months (range 24-111). All patients were in remission on immunosuppressive monotherapy for a minimum of 2 years before treatment was withdrawn. Using this strict approach, 15 patients (54%) remained in long-term remission after a median of 28 months follow-up (range 17-57) and 13 patients (46%) required reinstitution of treatment. Higher ALT and IgG levels - although within the normal range in all patients--were associated with the time to relapse. All patients who remained in remission had ALT levels less than half the ULN and IgG levels not higher than 12 g/L at the time of treatment withdrawal.

Conclusions: Proper patient selection including a sustained complete biochemical remission on immunosuppressive monotherapy for a minimum of 2 years can markedly improve the success rates of treatment withdrawal. The interpretation of aminotransferase and IgG levels within the normal range could aid in predicting the risk of relapse.
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http://dx.doi.org/10.1016/j.jhep.2014.10.018DOI Listing
March 2015

Transient elastography in primary sclerosing cholangitis-the value as a prognostic factor and limitations.

Gastroenterology 2014 Aug 25;147(2):542-3. Epub 2014 Jun 25.

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

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http://dx.doi.org/10.1053/j.gastro.2014.04.058DOI Listing
August 2014

PSC: Novel disease associations providing pathogenetic clues?

J Hepatol 2014 Apr 14;60(4):687-8. Epub 2014 Jan 14.

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

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http://dx.doi.org/10.1016/j.jhep.2014.01.005DOI Listing
April 2014

Primary sclerosing cholangitis and cholangiocarcinoma: pathogenesis and modes of diagnostics.

Dig Dis 2013 17;31(1):118-25. Epub 2013 Jun 17.

Collaborative Research Centre 841, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease caused by progressive inflammation of the intra- and extrahepatic bile duct system. PSC patients have an increased risk to develop hepatobiliary as well as extrahepatic malignancies. The goal of a surveillance strategy for hepatobiliary malignancy in these patients is the detection of early cancer which will allow a potentially curative therapy. Here, we focus on a conceptual review of the pathogenesis of cholangiocellular carcinoma and gallbladder cancer and we will discuss a rational approach for the surveillance of these malignancies in PSC patients.
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http://dx.doi.org/10.1159/000347206DOI Listing
October 2013

c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis.

Sci Signal 2012 Dec 18;5(255):ra93. Epub 2012 Dec 18.

Department of Immunology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.

As a catalytically inactive homolog of caspase-8, a proapoptotic initiator caspase, c-FLIP blocks apoptosis by binding to and inhibiting caspase-8. The transcription factor nuclear factor κB (NF-κB) plays a pivotal role in maintaining the homeostasis of the intestine and the liver by preventing death receptor-induced apoptosis, and c-FLIP plays a role in the NF-κB-dependent protection of cells from death receptor signaling. Because c-Flip-deficient mice die in utero, we generated conditional c-Flip-deficient mice to investigate the contribution of c-FLIP to homeostasis of the intestine and the liver at developmental and postnatal stages. Intestinal epithelial cell (IEC)- or hepatocyte-specific deletion of c-Flip resulted in perinatal lethality as a result of the enhanced apoptosis and programmed necrosis of the IECs and the hepatocytes. Deficiency in the gene encoding tumor necrosis factor-α (TNF-α) receptor 1 (Tnfr1) partially rescued perinatal lethality and the development of colitis in IEC-specific c-Flip-deficient mice but did not rescue perinatal lethality in hepatocyte-specific c-Flip-deficient mice. Moreover, adult mice with interferon (IFN)-inducible deficiency in c-Flip died from hepatitis soon after depletion of c-FLIP. Pretreatment of IFN-inducible c-Flip-deficient mice with a mixture of neutralizing antibodies against TNF-α, Fas ligand (FasL), and TNF-related apoptosis-inducing ligand (TRAIL) prevented hepatitis. Together, these results suggest that c-FLIP controls the homeostasis of IECs and hepatocytes by preventing cell death induced by TNF-α, FasL, and TRAIL.
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http://dx.doi.org/10.1126/scisignal.2003558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465294PMC
December 2012

Hepatocyte IKK2 protects Mdr2-/- mice from chronic liver failure.

PLoS One 2011 14;6(10):e25942. Epub 2011 Oct 14.

Institute for Genetics, Centre for Molecular Medicine (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

Unlabelled: Mice lacking the Abc4 protein encoded by the multidrug resistance-2 gene (Mdr2(-/-)) develop chronic periductular inflammation and cholestatic liver disease resulting in the development of hepatocellular carcinoma (HCC). Inhibition of NF-κB by expression of an IκBα super-repressor (IκBαSR) transgene in hepatocytes was shown to prevent HCC development in Mdr2(-/-) mice, suggesting that NF-κB acts as a tumour promoter in this model of inflammation-associated carcinogenesis. On the other hand, inhibition of NF-κB by hepatocyte specific ablation of IKK2 resulted in increased liver tumour development induced by the chemical carcinogen DEN. To address the role of IKK2-mediated NF-κB activation in hepatocytes in the pathogenesis of liver disease and HCC in Mdr2(-/-) mice, we generated Mdr2-deficient animals lacking IKK2 specifically in hepatocytes using the Cre-loxP system. Mdr2(-/-) mice lacking IKK2 in hepatocytes developed spontaneously a severe liver disease characterized by cholestasis, major hyperbilirubinemia and severe to end-stage fibrosis, which caused muscle wasting, loss of body weight, lethargy and early spontaneous death. Cell culture experiments showed that primary hepatocytes lacking IKK2 were more sensitive to bile acid induced death, suggesting that hepatocyte-specific IKK2 deficiency sensitized hepatocytes to the toxicity of bile acids under conditions of cholestasis resulting in greatly exacerbated liver damage. Mdr2(-/-)IKK2(Hep-KO) mice remarkably recapitulate chronic liver failure in humans and might be of special importance for the study of the mechanisms contributing to the pathogenesis of end-stage chronic liver disease or its implications on other organs.

Conclusion: IKK2-mediated signaling in hepatocytes protects the liver from damage under conditions of chronic inflammatory cholestasis and prevents the development of severe fibrosis and liver failure.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0025942PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195080PMC
February 2012

Humoral immune response against melanoma antigens induced by vaccination with cytokine gene-modified autologous tumor cells.

Int J Cancer 2004 Jan;108(2):307-13

German Cancer Research Center (DKFZ), Skin Cancer Unit (D070), Heidelberg, Germany.

Although the existence of a humoral response against tumor-associated antigens is well appreciated, a systematic analysis of its possible induction by the tumor remains missing. We compared the specific IgG response of Stage IV melanoma patients during vaccination. Patients had been treated within 2 clinical trials with autologous tumor cells gene-modified for IL-7 or IL-12. A panel of 27 tumor-associated antigens (HD-MM-01 to HD-MM-27) was isolated by a SEREX screening of a testis cDNA library using a pool of 5 sera from patients after vaccination. All antigens were retested with individual sera of 12 patients both pre- and post-vaccination. A serological response was induced during vaccination against 18 antigens. Remarkably, induction was detected only in patients included in the screening pool. The low overlap between sero-reactivity of the 12 patients suggested a very individualized immunological reaction. Two of 5 sera included in the screening pool exhibited a high frequency of induced humoral responses. The same patients had been shown to have a high Karnovsky index and had generated lytic cytotoxic T cells against the tumor. Besides 2 known cancer-germline genes (SCP-1 and PLU-1), the other isolated antigens were expressed in a non-tumor-specific fashion as analyzed by virtual Northern blot or RT-PCR. The properties of homologues to several of the identified tumor-antigens, especially PLU-1, SCP-1, DNEL2, CLOCK, and PIASx-alpha, suggest further investigation of their possible function in malignant melanoma. We conclude that a strong humoral response against tumor-associated antigens is inducible by tumor cells and that this response is very individual.
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http://dx.doi.org/10.1002/ijc.11537DOI Listing
January 2004