Publications by authors named "Benjamin Maasoumy"

82 Publications

Editorial: percutaneous placement of a permanent tunnelled catheter for patients with non-malignant ascites - is it safe? Authors' reply.

Aliment Pharmacol Ther 2022 Sep;56(5):911

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

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http://dx.doi.org/10.1111/apt.17157DOI Listing
September 2022

Letter: long-term abdominal drains in cirrhosis-a solution or a new problem? Authors' reply.

Aliment Pharmacol Ther 2022 Sep;56(5):926-927

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

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http://dx.doi.org/10.1111/apt.17168DOI Listing
September 2022

Metamizole-Associated Risks in Decompensated Hepatic Cirrhosis.

Dtsch Arztebl Int 2022 Sep 30(Forthcoming). Epub 2022 Sep 30.

Background: Because of the increased risk of acute renal failure (ARF), the use of cyclooxygenase (COX) inhibitors is not recommended in patients with decompensated hepatic cirrhosis. Metamizole is not a classic COX inhibitor, but there are insufficient data to support its safe use. In this study, we investigate the effect of metamizole on the risk of ARF in these patients.

Methods: Metamizole use, ARF incidence, and patient mortality were examined in a large, retrospective, exploratory cohort and validated with data from a prospective registry.

Results: 523 patients were evaluated in the exploratory cohort. Metamizole use at baseline was documented in 110 cases (21%) and was independently associated with the development of ARF, severe (grade 3) ARF, and lower survival without liver transplantation at follow-up on day 28 (HR: 2.2, p < 0.001; HR: 2.8, p < 0.001; and HR: 2.6, p < 0.001, respectively). Interestingly, the risk of ARF depended on the dose of metamizole administered (HR: 1.038, p < 0.001). Compared to patients who were treated with opioids, the rate of ARF was higher in the metamizole group (49% vs. 79%, p = 0.014). An increased risk of ARF with metamizole use was also demonstrated in the independent validation cohort (p < 0.001).

Conclusion: Metamizole therapy, especially at high doses, should only be used with a high level of caution in patients with decompensated cirrhosis.
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http://dx.doi.org/10.3238/arztebl.m2022.0280DOI Listing
September 2022

Reply to: "Probability of HBsAg loss after nucleos(t)ide analogue withdrawal depends on HBV genotype and viral antigen levels".

J Hepatol 2022 Jul 8. Epub 2022 Jul 8.

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

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http://dx.doi.org/10.1016/j.jhep.2022.06.028DOI Listing
July 2022

Direct-Acting Antiviral Agents for Hepatitis C Virus Infection-From Drug Discovery to Successful Implementation in Clinical Practice.

Viruses 2022 06 17;14(6). Epub 2022 Jun 17.

Department of Gastroenterology, Hepatology and Endocrinology, Medical High School Hannover, 30625 Hannover, Germany.

Today, hepatitis C virus infection affects up to 1.5 million people per year and is responsible for 29 thousand deaths per year. In the 1970s, the clinical observation of unclear, transfusion-related cases of hepatitis ignited scientific curiosity, and after years of intensive, basic research, the hepatitis C virus was discovered and described as the causative agent for these cases of unclear hepatitis in 1989. Even before the description of the hepatitis C virus, clinicians had started treating infected individuals with interferon. However, intense side effects and limited antiviral efficacy have been major challenges, shaping the aim for the development of more suitable and specific treatments. Before direct-acting antiviral agents could be developed, a detailed understanding of viral properties was necessary. In the years after the discovery of the new virus, several research groups had been working on the hepatitis C virus biology and finally revealed the replication cycle. This knowledge was the basis for the later development of specific antiviral drugs referred to as direct-acting antiviral agents. In 2011, roughly 22 years after the discovery of the hepatitis C virus, the first two drugs became available and paved the way for a revolution in hepatitis C therapy. Today, the treatment of chronic hepatitis C virus infection does not rely on interferon anymore, and the treatment response rate is above 90% in most cases, including those with unsuccessful pretreatments. Regardless of the clinical and scientific success story, some challenges remain until the HCV elimination goals announced by the World Health Organization are met.
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http://dx.doi.org/10.3390/v14061325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9231290PMC
June 2022

Home-based, tunnelled peritoneal drainage system as an alternative treatment option for patients with refractory ascites.

Aliment Pharmacol Ther 2022 Aug 2;56(3):529-539. Epub 2022 Jun 2.

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

Background: Onset of refractory ascites is the hallmark of end-stage liver disease. If liver transplantation (LTx) is not available and contraindications for a transjugular portosystemic shunt (TIPS) are present, repeated paracentesis remains the standard of care (SOC). Home-based, tunnelled peritoneal catheters (PeCa) have been suggested as an alternative treatment option. However, data on patients with cirrhosis are scarce.

Aim: To evaluate the safety of PeCa in these patients compared to SOC.

Methods: Overall, 223 patients with cirrhosis, a contraindication for TIPS and refractory ascites were included in this retrospective study. PeCa implant was performed in 152 patients, whereas 71 were treated with SOC. Analysed end points included device explant-free survival, mortality, acute kidney injury (AKI) and hyponatraemia. In the second approach, propensity score matching (PPSM) was performed to adjust for confounding factors.

Results: In patients with PeCa, median device explant-free survival was 74 days and 52 explants were recorded within the first 90 days. Within 90 days, patients with PeCa had lower mortality than SOC (p = 0.11), and spontaneous bacterial peritonitis (SBP) incidence did not differ (p = 0.82). Regarding AKI and hyponatraemia, there was a trend towards a higher incidence in the PeCa group (p = 0.13 and p = 0.08), and the risk for rehospitalisation was higher in those with a PeCa (HR: 2.11, p = 0.04). After PPSM, mortality was lower in the PeCa group (HR:0.40; p = 0.03), whereas the incidence of SBP and hyponatraemia was comparable (p = 0.80 and p = 0.28) and AKI was more frequent in those with a PeCa (p = 0.08).

Conclusion: The implant of PeCa allows home-based therapy of patients with cirrhosis and refractory ascites and a contraindication for TIPS. However, the risk for complications has to be considered and prospective studies are needed.
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http://dx.doi.org/10.1111/apt.17066DOI Listing
August 2022

FIB-4 and APRI as Predictive Factors for Short- and Long-Term Survival in Patients with Transjugular Intrahepatic Portosystemic Stent Shunts.

Biomedicines 2022 Apr 28;10(5). Epub 2022 Apr 28.

Department of Gastroenterology and Hepatology, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany.

(1) Background: Transjugular intrahepatic portosystemic shunt (TIPS) is a standard therapy for portal hypertension. We aimed to explore the association of established baseline scores with TIPS outcomes. (2) Methods: In total, 136 liver cirrhosis patients underwent TIPS insertion, mainly to treat refractory ascites (86%), between January 2016 and December 2019. An external validation cohort of 187 patients was chosen. (3) Results: The majority of the patients were male (62%); the median follow-up was 715 days. The baseline Child-Turcotte-Pugh stage was A in 14%, B in 75% and C in 11%. The patients' liver-transplant-free (LTF) survival rates after 3, 12 and 24 months were 87%, 72% and 61%, respectively. In the univariate analysis, neither bilirubin, nor the international normalized ratio (INR), nor liver enzymes were associated with survival. However, both the APRI (AST-to-platelet ratio index) and the FIB-4 (fibrosis-4 score) were associated with LTF survival. For patients with FIB-4 > 3.25, the hazard ratio for mortality after 2 years was 3.952 ( < 0.0001). Liver-related clinical events were monitored for 24 months. High FIB-4 scores were predictive of liver-related events (HR = 2.404, = 0.001). Similarly, in our validation cohort, LTF survival was correlated with the APRI and FIB-4 scores. (4) Conclusions: Well-established scores that reflect portal hypertension and biochemical disease activity predict long-term outcomes after TIPS and support clinical decisions over TIPS insertion.
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http://dx.doi.org/10.3390/biomedicines10051018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9138812PMC
April 2022

Breakthroughs in hepatitis C research: from discovery to cure.

Nat Rev Gastroenterol Hepatol 2022 Aug 20;19(8):533-550. Epub 2022 May 20.

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

In the 1970s, an unknown virus was suspected for documented cases of transfusion-associated hepatitis, a phenomenon called non-A, non-B hepatitis. In 1989, the infectious transmissible agent was identified and named hepatitis C virus (HCV) and, soon enough, the first diagnostic HCV antibody test was developed, which led to a dramatic decrease in new infections. Today, HCV infection remains a global health burden and a major cause of liver cirrhosis, hepatocellular carcinoma and liver transplantation. However, tremendous advances have been made over the decades, and HCV became the first curable, chronic viral infection. The introduction of direct antiviral agents revolutionized antiviral treatment, leading to viral eradication in more than 98% of all patients infected with HCV. This Perspective discusses the history of HCV research, which reads like a role model for successful translational research: starting from a clinical observation, specific therapeutic agents were developed, which finally were implemented in national and global elimination programmes.
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http://dx.doi.org/10.1038/s41575-022-00608-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9122245PMC
August 2022

[Peracute Diseases of the Esophagus - Bleeding from Esophageal Varices, Esophageal Varices].

Ther Umsch 2022 Apr;79(3-4):212-216

Klinik für Allgemeinchirurgie, Viszeral-, Thorax-, Kinder- und Endokrine Chirurgie, Mühlenkreiskliniken, Universitätsklinikum der Ruhr-Universität Bochum, Minden, Deutschland.

Peracute Diseases of the Esophagus - Bleeding from Esophageal Varices, Esophageal Varices Due to a permanently increased portal venous pressure - usually due to infectious or ethyltoxic liver cirrhosis - varices can form in the lower esophagus due to expansion of the submucosal venous plexus. Acute bleeding from the esophageal varices is a life-threatening situation. In therapy, a distinction is made between primary prophylaxis of bleeding, control of acute bleeding and prevention of recurrent bleeding. In addition to non-selective betablockers, the transjugular intrahepatic portosystemic shunt (TIPS), which is introduced radiologically, plays a decisive role today, especially in the prophylaxis of recurrent bleeding. Apart from special indications, surgical shunt procedures are only of historical value. In liver cirrhosis patients, liver transplantation represents a causal treatment and lasting cure for esophageal varices.
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http://dx.doi.org/10.1024/0040-5930/a001351DOI Listing
April 2022

Nosocomial infections in female compared with male patients with decompensated liver cirrhosis.

Sci Rep 2022 02 28;12(1):3285. Epub 2022 Feb 28.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.

There are considerable differences between males and females regarding the etiology, progression and outcome of liver diseases. Infections are a frequent and severe complication in these patients. This study aimed to examine sex specific differences in the incidence and clinical course of nosocomial infections in patients with decompensated liver cirrhosis. A number of 556 consecutive hospitalized patients with decompensated liver cirrhosis and ascites were analyzed. The patients were followed up for the incidence of nosocomial infections, acute kidney injury (AKI), acute-on-chronic liver failure (ACLF) as well as liver transplantation and death (LTx-free survival). A number of 285 patients (111 women and 174 men) developed a nosocomial infection. Incidence was numerically lower in men (P = 0.076). While the frequency of a nosocomial spontaneous bacterial peritonitis was similar between males and females, the incidence of a nosocomial urinary tract infection was significantly higher in women (P < 0.001). No sex specific differences were documented regarding the outcome of an infection as indicated by a similar incidence of, AKI, ACLF as well as LTx-free survival. There seem to be no major differences in the incidence and outcome of nosocomial infections between male and female patients.
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http://dx.doi.org/10.1038/s41598-022-07084-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8885665PMC
February 2022

[Raw meat, lots of problems: rare infection in a patient after mechanical valve replacement and liver transplantation].

Inn Med (Heidelb) 2022 Jun 17;63(6):658-661. Epub 2022 Feb 17.

Zentrale Notaufnahme und internistische IMC-Station, Medizinische Hochschule Hannover, Hannover, Deutschland.

We report about a 43-year-old man who presented to the emergency department in septic shock with nonspecific gastrointestinal symptoms. Sonography and computed tomography (CT) could not identify the location of the infection in the patient who had undergone liver transplantation and has a mechanical mitral valve. Blood cultures were positive for Listeria monocytogenes. Transesophageal echocardiography showed prosthetic endocarditis. The findings regressed markedly under ampicillin.
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http://dx.doi.org/10.1007/s00108-022-01279-yDOI Listing
June 2022

Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels.

J Hepatol 2022 05 29;76(5):1042-1050. Epub 2022 Jan 29.

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

Background & Aims: Nucleo(s)tide analogue (NUC) withdrawal may result in HBsAg clearance in a subset of patients. However, predictors of HBsAg loss after NUC withdrawal remain ill-defined.

Methods: We studied predictors of HBsAg loss in a global cohort of HBeAg-negative patients with undetectable HBV DNA who discontinued long-term NUC therapy. Patients requiring retreatment after treatment cessation were considered non-responders.

Results: We enrolled 1,216 patients (991 with genotype data); 98 (8.1%) achieved HBsAg loss. The probability of HBsAg loss was higher in non-Asian patients (adjusted hazard ratio [aHR] 8.26, p <0.001), and in patients with lower HBsAg (aHR 0.243, p <0.001) and HBV core-related antigen (HBcrAg) (aHR 0.718, p = 0.001) levels. Combining HBsAg (<10, 10-100 or >100 IU/ml) and HBcrAg (<2log vs. ≥2 log) levels improved prediction of HBsAg loss, with extremely low rates observed in patients with HBsAg >100 IU/ml with detectable HBcrAg. HBsAg loss rates also varied with HBV genotype; the highest rates were observed for genotypes A and D, and none of the patients with HBV genotype E experienced HBsAg loss (p <0.001 for the overall comparison across genotypes; p <0.001 for genotypes A/D vs. genotypes B/C). HBV genotype C was independently associated with a higher probability of HBsAg loss when compared to genotype B among Asian patients (aHR 2.494; 95% CI 1.490-4.174, p = 0.001).

Conclusions: The probability of HBsAg loss after NUC cessation varies according to patient ethnicity, HBV genotype and end-of-treatment viral antigen levels. Patients with low HBsAg (<100 IU/ml) and/or undetectable HBcrAg levels, particularly if non-Asian or infected with HBV genotype C, appear to be the best candidates for treatment withdrawal.

Lay Summary: A subset of patients may achieve clearance of hepatitis B surface antigen (HBsAg) - so-called functional cure - after withdrawal of nucleo(s)tide analogue therapy. In this multicentre study of 1,216 patients who discontinued antiviral therapy, we identified non-Asian ethnicity, HBV genotype C, and low hepatitis B surface antigen and hepatitis B core-related antigen levels as factors associated with an increased chance of HBsAg loss.
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http://dx.doi.org/10.1016/j.jhep.2022.01.007DOI Listing
May 2022

Hepatitis E virus is highly resistant to alcohol-based disinfectants.

J Hepatol 2022 05 24;76(5):1062-1069. Epub 2022 Jan 24.

Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany; German Centre for Infection Research (DZIF), External Partner Site, Bochum, Germany. Electronic address:

Background & Aims: Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis worldwide and is mainly transmitted via the fecal-oral route or through consumption of contaminated food products. Due to the lack of efficient cell culture systems for the propagation of HEV, limited data regarding its sensitivity to chemical disinfectants are available. Consequently, preventive and evidence-based hygienic guidelines on HEV disinfection are lacking.

Methods: We used a robust HEV genotype 3 cell culture model which enables quantification of viral infection of quasi-enveloped and naked HEV particles. For HEV genotype 1 infections, we used the primary isolate Sar55 in a fecal suspension. Standardized quantitative suspension tests using end point dilution and large-volume plating were performed for the determination of virucidal activity of alcohols (1-propanol, 2-propanol, ethanol), WHO disinfectant formulations and 5 different commercial hand disinfectants against HEV. Iodixanol gradients were conducted to elucidate the influence of ethanol on quasi-enveloped viral particles.

Results: Naked and quasi-enveloped HEV was resistant to alcohols as well as alcohol-based formulations recommended by the WHO. Of the tested commercial hand disinfectants only 1 product displayed virucidal activity against HEV. This activity could be linked to phosphoric acid as an essential ingredient. Finally, we observed that ethanol and possibly non-active alcohol-based disinfectants disrupt the quasi-envelope structure of HEV particles, while leaving the highly transmissible and infectious naked virions intact.

Conclusions: Different alcohols and alcohol-based hand disinfectants were insufficient to eliminate HEV infectivity with the exception of 1 commercial ethanol-based product that included phosphoric acid. These findings have major implications for the development of measures to reduce viral transmission in clinical practice.

Lay Summary: Hepatitis E virus (HEV) showed a high level of resistance to alcohols and alcohol-based hand disinfectants. The addition of phosphoric acid to alcohol was essential for virucidal activity against HEV. This information should be used to guide improved hygiene measures for the prevention of HEV transmission.
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http://dx.doi.org/10.1016/j.jhep.2022.01.006DOI Listing
May 2022

Prevalence of hepatitis D virus co-infection in Austria - Finding the needle in the haystack.

United European Gastroenterol J 2021 12 24;9(10):1105-1106. Epub 2021 Nov 24.

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

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http://dx.doi.org/10.1002/ueg2.12177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672078PMC
December 2021

Impact of HBsAg and HBcrAg levels on phenotype and function of HBV-specific T cells in patients with chronic hepatitis B virus infection.

Gut 2021 Oct 26. Epub 2021 Oct 26.

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

Objective: Hepatitis B virus (HBV)-specific T cells are main effector cells in the control of HBV infection and hepatitis B surface antigen (HBsAg) is suggested to be a critical factor in the impaired immune response, a hallmark of chronic HBV infection. In addition to HBsAg, other viral markers such as hepatitis B core-related antigen (HBcrAg) are available, but their potential association with HBV-specific immune responses is not defined yet, which will be important if these markers are used for patient stratification for novel therapies aimed at functional HBV cure.

Design: We analysed T cell responses in 92 patients with hepatitis B e antigen negative chronic HBV infection with different HBsAg and HBcrAg levels. Overlapping peptides were used for in vitro response analyses (n=57), and HBV core-specific and polymerase (pol)-specific CD8 T cells were assessed in human leukocyte antigen (HLA)-A*02 patients (n=35). In addition, in vitro responsiveness to anti-programmed cell death-ligand 1 (anti-PD-L1) was investigated.

Results: HBV-specific T cell responses were not affected by HBsAg levels, but rather by age and CD4 T cell responses were highest in patients with low HBcrAg levels. The phenotypes and functionality of HBV core-specific and pol-specific CD8 T cells differed, but HBsAg and HBcrAg levels did not affect their profiles. Blocking with anti-PD-L1 could restore HBV-specific T cells, but the effect was significantly higher in T cells isolated from patients with low HBsAg and in particular low HBcrAg.

Conclusion: Our data suggest that age and HBcrAg rather than HBsAg, are associated with HBV-specific T cell responses. Finally, very low antigen levels indicated by HBsAg and in particular HBcrAg may influence T cell response to checkpoint inhibition.
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http://dx.doi.org/10.1136/gutjnl-2021-324646DOI Listing
October 2021

[Glecaprevir/Pibrentasvir + Sofosbuvir + Ribavirin as a salvage regimen after Sofosbuvir + Velpatasvir + Voxilaprevir re-treatment failure].

Z Gastroenterol 2022 Jun 19;60(6):959-962. Epub 2021 Oct 19.

Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Deutschland.

Antiviral therapy of chronic hepatitis C virus (HCV) achieves sustained virological response (SVR) in the majority of patients. Even after initial virological failure, re-treatment with the combination of sofosbuvir+velpatasvir+voxilaprevir (SOF/VEL/VOX) has been established as an effective second line regimen. However, some patients fail to achieve SVR after a second antiviral course with SOF/VEL/VOX. These patients are considered difficult-to-cure. Currently, the optimal regimen for antiviral re-re-treamtent is a matter of debate and European and American guidelines suggest the combination of SOF+glecaprevir/pibrentasvir (G/P) + Ribavirin as a salvage regimen. However, there is only little evidence to support this. In this study, data of two patients with genotype 3 chronic HCV infection, liver cirrhosis and virological failure after re-treatment with SOF/VEL/VOX that successfully achieved SVR with the combination of SOF+G/P ± RBV. Importantly, one patient had Child B cirrhosis to the time of treatment initiation. No adverse events were reported. Thus, our data support the use of SOF + G/P + RBV as a salvage regimen after re-treatment failure with SOF/VEL/VOX.
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http://dx.doi.org/10.1055/a-1649-8931DOI Listing
June 2022

Low Serum Cholinesterase Identifies Patients With Worse Outcome and Increased Mortality After TIPS.

Hepatol Commun 2022 03 28;6(3):621-632. Epub 2021 Sep 28.

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

Transjugular intrahepatic portosystemic shunt (TIPS) is an effective treatment for portal hypertension-related complications. However, careful selection of patients is crucial. The aim of this study was to evaluate the prognostic value of serum cholinesterase (CHE) for outcomes and mortality after TIPS insertion. In this multicenter study, 389 consecutive patients with cirrhosis receiving a TIPS at Hannover Medical School, University Hospital Essen, or Medical University of Vienna were included. The Hannover cohort (n = 200) was used to initially explore the role of CHE, whereas patients from Essen and Vienna served as a validation cohort (n = 189). Median age of the patients was 58 years and median Model for End-Stage Liver Disease (MELD) score was 12. Multivariable analysis identified MELD score (hazard ratio [HR]: 1.16; P < 0.001) and CHE (HR: 0.61; P = 0.008) as independent predictors for 1-year survival. Using the Youden Index, a CHE of 2.5 kU/L was identified as optimal threshold to predict post-TIPS survival in the Hannover cohort (P < 0.001), which was confirmed in the validation cohort (P = 0.010). CHE < 2.5 kU/L was significantly associated with development of acute-on-chronic liver failure (P < 0.001) and hepatic encephalopathy (P = 0.006). Of note, CHE was also significantly linked to mortality in the subgroup of patients with refractory ascites (P = 0.001) as well as in patients with high MELD scores (P = 0.012) and with high-risk FIPS scores (P = 0.004). After propensity score matching, mortality was similar in patients with ascites and CHE < 2.5 kU/L if treated by TIPS or by paracentesis. Contrarily, in patients with CHE ≥ 2.5 kU/L survival was significantly improved by TIPS as compared to treatment with paracentesis (P < 0.001). Conclusion: CHE is significantly associated with mortality and complications after TIPS insertion. Therefore, we suggest that CHE should be evaluated as an additional parameter for selecting patients for TIPS implantation.
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http://dx.doi.org/10.1002/hep4.1829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870033PMC
March 2022

HBcrAg Levels Are Associated With Virological Response to Treatment With Interferon in Patients With Hepatitis Delta.

Hepatol Commun 2022 03 24;6(3):480-495. Epub 2021 Sep 24.

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

Standard treatment of hepatitis delta virus (HDV) infection remains pegylated-interferon alfa (peg-IFNα) in most centers, which is not only associated with rather low efficacy but several adverse events. Hepatitis B core-related antigen (HBcrAg) is linked to intrahepatic covalently closed circular DNA levels and has previously been suggested as response predictor in IFN-based treatment of hepatitis B virus (HBV) mono-infection. This study aimed to investigate the value of HBcrAg in the management of patients with HBV/HDV co-infection undergoing peg-IFNα treatment. The Hep-Net-International-Delta-Hepatitis-Intervention Trial-2 study included 120 patients co-infected with HBV/HDV. Patients were treated for 96 weeks with peg-IFNα and either tenofovir or placebo. Ninety-nine patients with HDV-RNA results 24 weeks after end of treatment (FU24) were included in this analysis, of whom 32 patients (32.3%) had undetectable HDV RNA at FU24. HBcrAg was measured at baseline, week 12, 24, 48, 96, and FU24. HBcrAg levels showed no significant correlation with HDV RNA but were significantly linked to treatment outcome. HBcrAg levels < 4.5 log IU/mL at baseline, week 24, and week 48 had high negative predictive value (NPV) for achieving undetectable HDV RNA at FU24 (81.8%, 87.1% and 95.0%, respectively). Similarly, HBcrAg levels at week 96 were significantly higher in patients with viral relapse until FU24 (3.0 vs. 3.63 log IU/mL; P = 0.0089). Baseline, week 24, and week 48 HBcrAg levels were also associated with the likelihood of achieving HBsAg level < 100 IU/mL at FU24 (HBcrAg < 3.0 log IU/mL: NPV 91.7%, 90.4% and 92.3%, respectively). Test statistics improved when combining HBcrAg with additional viral and clinical parameters. Conclusion: HBcrAg is linked to treatment response to peg-IFNα in patients with HBV/HDV co-infection and could be a promising marker to determine treatment futility.
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http://dx.doi.org/10.1002/hep4.1821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870014PMC
March 2022

Impact of the COVID-19 pandemic on patients with liver cirrhosis-the experience of a tertiary center in Germany.

Z Gastroenterol 2021 Sep 10;59(9):954-960. Epub 2021 Sep 10.

Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Background: The COVID-19 pandemic has caused a significant impact on the medical care of many diseases and has led to reduced presentations to the emergency department. Reduced presentations may be due to overwhelmed capacities of hospitals or collateral damage from fear of infection, lockdown regulations, or other reasons. The effect on patients with liver cirrhosis is not established.

Objective: We aim to assess the impact on the care of patients with liver cirrhosis in a tertiary center in Northern Germany.

Methods: All patients presenting to the emergency department with a diagnosis of cirrhosis between March 1 and May 31 from 2015-2020 were included. Reasons for presentation, duration of symptoms, the severity of liver disease, and 30-day mortality were assessed and compared between patients presenting during the COVID-19 pandemic and pre-COVID-19.

Results: Overall, 235 patients were included. Despite an overall decline in presentations to the emergency department by 11.7%, the frequency of patients presenting with liver cirrhosis has remained stable (non-significant increase by 19.5%). No significant difference could be detected for the MELD score, the CLIF-organ failure subscores, and the 30-day mortality before and during the COVID-19 pandemic. Up to 75% of patients with liver cirrhosis had symptoms >24 h before presenting to the emergency department.

Conclusion: Despite the overall trend of reduced emergency presentations during the COVID-19 pandemic, the frequency of presentations of patients with liver cirrhosis did not decline. Morbidity and mortality were not affected in a setting of disposable healthcare resources. The late presentation to the emergency department in many cirrhotic patients may open opportunities for interventions (i.e., with early telemedicine intervention).
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http://dx.doi.org/10.1055/a-1540-7726DOI Listing
September 2021

Quantification of polyreactive immunoglobulin G facilitates the diagnosis of autoimmune hepatitis.

Hepatology 2022 01 5;75(1):13-27. Epub 2021 Dec 5.

European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany.

Background And Aims: Detection of autoantibodies is a mainstay of diagnosing autoimmune hepatitis (AIH). However, conventional autoantibodies for the workup of AIH lack either sensitivity or specificity, leading to substantial diagnostic uncertainty. We aimed to identify more accurate serological markers of AIH with a protein macroarray.

Approach And Results: During the search for more-precise autoantibodies to distinguish AIH from non-AIH liver diseases (non-AIH-LD), IgG antibodies with binding capacities to many human and foreign proteins were identified with a protein macroarray and confirmed with solid-phase ELISAs in AIH patients. Subsequently, polyreactive IgG (pIgG) was exemplarily quantified by reactivity against human huntingtin-interacting protein 1-related protein in bovine serum albumin blocked ELISA (HIP1R/BSA). The diagnostic fidelity of HIP1R/BSA binding pIgG to diagnose AIH was assessed in a retrospective training, a retrospective multicenter validation, and a prospective validation cohort in cryoconserved samples from 1,568 adults from 10 centers from eight countries. Reactivity against HIP1R/BSA had a 25% and 14% higher specificity to diagnose AIH than conventional antinuclear and antismooth muscle antibodies, a significantly higher sensitivity than liver kidney microsomal antibodies and antisoluble liver antigen/liver pancreas antigen, and a 12%-20% higher accuracy than conventional autoantibodies. Importantly, HIP1R/BSA reactivity was present in up to 88% of patients with seronegative AIH and in up to 71% of AIH patients with normal IgG levels. Under therapy, pIgG returns to background levels of non-AIH-LD.

Conclusions: pIgG could be used as a promising marker to improve the diagnostic workup of liver diseases with a higher specificity for AIH compared to conventional autoantibodies and a utility in autoantibody-negative AIH. Likewise, pIgG could be a major source of assay interference in untreated AIH.
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http://dx.doi.org/10.1002/hep.32134DOI Listing
January 2022

Reaching the Unreachable: Strategies for HCV Eradication in Patients With Refractory Opioid Addiction-A Real-world Experience.

Open Forum Infect Dis 2021 Aug 17;8(8):ofab325. Epub 2021 Jun 17.

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

To achieve global hepatitis C virus (HCV) eradication, barriers prohibiting treatment access need to be overcome. We established a strategy to initiate antiviral therapy in patients with severe, refractory heroin addiction. All patients achieved sustained virological response. Outreach programs of hepatologists might be a reasonable way to overcome barriers to HCV treatment.
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http://dx.doi.org/10.1093/ofid/ofab325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339280PMC
August 2021

Reliable quantification of plasma HDV RNA is of paramount importance for treatment monitoring: A European multicenter study.

J Clin Virol 2021 09 24;142:104932. Epub 2021 Jul 24.

Research Unit Molecular Diagnostics, Diagnostic and Research Center for Molecular Biomedicine, Medical University of Graz, Austria. Electronic address:

Objectives: Quantification of plasma hepatitis D virus (HDV) RNA is the essential tool for patient management under antiviral therapy. The aim of this European multicenter study was to improve the comparability of quantitative results reported by different laboratories using the CE/IVD-labeled RoboGene HDV RNA Quantification Kit 2.0 (Roboscreen GmbH) with different manual or automated nucleic acid extraction protocols/platforms and amplification/detection devices.

Methods: For harmonization of HDV RNA concentrations obtained by different protocols, correction factors (CF) were determined using the 1st WHO International Standard for HDV RNA. The limit of detection (LOD) and accuracy were determined for each protocol by using reference material. Furthermore, clinical samples were analyzed and results compared.

Results: The CF ranged from 20 to 1,870 depending on the protocol used. The LOD was found between 4 and 450 IU/ml. When accuracy was tested, external quality control (EQC) samples containing low HDV RNA concentrations were not detected by those protocols with higher LODs. For EQC samples, the maximum standard deviation of HDV RNA concentrations was found to be 0.53 log IU/ml, for clinical samples 0.87 log IU/mL.

Conclusion: To ensure reliability in quantification of HDV RNA, any modification of the extraction and amplification/detection protocol validated by the manufacturer requires revalidation. With the 1st WHO International Standard for HDV RNA, the CF could easily be calculated leading to harmonization of quantitative results. This warrants both accurate monitoring of response to existing anti-HDV treatment and comparability of study results investigating novel anti-HDV drugs.
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http://dx.doi.org/10.1016/j.jcv.2021.104932DOI Listing
September 2021

Prothrombotic immune thrombocytopenia after COVID-19 vaccination.

Blood 2021 07;138(4):350-353

Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

We report 5 cases of prothrombotic immune thrombocytopenia after exposure to the ChAdOx1 vaccine (AZD1222, Vaxzevria) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients presented 5 to 11 days after first vaccination. The spectrum of clinical manifestations included cerebral venous sinus thrombosis, splanchnic vein thrombosis, arterial cerebral thromboembolism, and thrombotic microangiopathy. All patients had thrombocytopenia and markedly elevated D-dimer. Autoantibodies against platelet factor 4 (PF4) were detected in all patients, although they had never been exposed to heparin. Immunoglobulin from patient sera bound to healthy donor platelets in an AZD1222-dependent manner, suppressed by heparin. Aggregation of healthy donor platelets by patient sera was demonstrated in the presence of buffer or AZD1222 and was also suppressed by heparin. Anticoagulation alone or in combination with eculizumab or intravenous immunoglobulin (IVIG) resolved the pathology in 3 patients. Two patients had thromboembolic events despite anticoagulation at a time when platelets were increasing after IVIG. In summary, an unexpected autoimmune prothrombotic disorder is described after vaccination with AZD1222. It is characterized by thrombocytopenia and anti-PF4 antibodies binding to platelets in AZD1222-dependent manner. Initial clinical experience suggests a risk of unusual and severe thromboembolic events.
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http://dx.doi.org/10.1182/blood.2021011958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084604PMC
July 2021

Plasma and ascites pharmacokinetics of meropenem in patients with decompensated cirrhosis and spontaneous bacterial peritonitis.

J Hepatol 2022 01 24;76(1):230-233. Epub 2021 Jul 24.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2021.07.015DOI Listing
January 2022

Antimicrobial resistance in patients with decompensated liver cirrhosis and bacterial infections in a tertiary center in Northern Germany.

BMC Gastroenterol 2021 Jul 20;21(1):296. Epub 2021 Jul 20.

Department for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

Background And Aims: Bacterial infections are common in patients with decompensated liver cirrhosis and a leading cause of death. Reliable data on antibiotic resistance are required to initiate effective empiric therapy. We here aim to assess the antimicrobial resistance profile of bacteria among patients with liver cirrhosis and infection.

Methods: Overall, 666 cirrhotic patients admitted to Hannover Medical School between January 2012 and April 2018 with ascites were assessed for bacterial infection. In case of infection, bacteria cultured from microbiological specimens of ascites, blood or urine were identified and analyzed for resistances against common antibiotic agents. Furthermore, analyses compared two periods of time and community-acquired vs. nosocomial infections.

Results: In 281 patients with infection, microbiological sampling was performed and culture-positive results were obtained in 56.9%. Multidrug-resistant (MDR)-bacteria were found in 54 patients (19.2%). Gram-positive organisms were more common (n = 141/261, 54.0%) and detected in 116/192 culture-positive infections (60.4%). Comparing infections before and after 2015, a numerical decline for MDR-bacteria (23.8% vs. 15.6%, p = 0.08) was observed with a significant decline in meropenem resistance (34.9% vs. 19.5%, p = 0.03). MDR-bacteria were more frequent in the case of nosocomial infections. Of note, in ascites the majority of the tested bacteria were resistant against ceftriaxone (73.8%) whereas significantly less were resistant against meropenem (27.0%) and vancomycin (25.9%).

Conclusions: In our tertiary center, distinct ratios of gram-positive infection with overall low ratios of MDR-bacteria were found. Adequate gram-positive coverage in the empiric therapy should be considered. Carbapenem treatment may be omitted even in nosocomial infection. In contrast, 3rd generation cephalosporins cannot be recommended even in community-acquired infection in our cirrhotic population.
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http://dx.doi.org/10.1186/s12876-021-01871-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290615PMC
July 2021

Interdependent Impact of Lipoprotein Receptors and Lipid-Lowering Drugs on HCV Infectivity.

Cells 2021 06 29;10(7). Epub 2021 Jun 29.

Centre for Experimental and Clinical Infection Research, Institute for Experimental Virology, TWINCORE, 30625 Hannover, Germany.

The HCV replication cycle is tightly associated with host lipid metabolism: Lipoprotein receptors SR-B1 and LDLr promote entry of HCV, replication is associated with the formation of lipid-rich membranous organelles and infectious particle assembly highjacks the very‑low-density lipoprotein (VLDL) secretory pathway. Hence, medications that interfere with the lipid metabolism of the cell, such as statins, may affect HCV infection. Here, we study the interplay between lipoprotein receptors, lipid homeostasis, and HCV infection by genetic and pharmacological interventions. We found that individual ablation of the lipoprotein receptors SR‑B1 and LDLr did not drastically affect HCV entry, replication, or infection, but double lipoprotein receptor knock-outs significantly reduced HCV infection. Furthermore, we could show that this effect was neither due to altered expression of additional HCV entry factors nor caused by changes in cellular cholesterol content. Strikingly, whereas lipid‑lowering drugs such as simvastatin or fenofibrate did not affect HCV entry or infection of immortalized hepatoma cells expressing SR-B1 and/or LDLr or primary human hepatocytes, ablation of these receptors rendered cells more susceptible to these drugs. Finally, we observed no significant differences between statin users and control groups with regards to HCV viral load in a cohort of HCV infected patients before and during HCV antiviral treatment. Interestingly, statin treatment, which blocks the mevalonate pathway leading to decreased cholesterol levels, was associated with mild but appreciable lower levels of liver damage markers before HCV therapy. Overall, our findings confirm the role of lipid homeostasis in HCV infection and highlight the importance of the mevalonate pathway in the HCV replication cycle.
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http://dx.doi.org/10.3390/cells10071626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303410PMC
June 2021

Only partial improvement in health-related quality of life after treatment of chronic hepatitis C virus infection with direct acting antivirals in a real-world setting-results from the German Hepatitis C-Registry (DHC-R).

J Viral Hepat 2021 08 8;28(8):1206-1218. Epub 2021 Jun 8.

Kreiskliniken Altötting-Burghausen, Burghausen, Germany.

Improvement of health-related quality of life (HRQoL) is frequently reported as a benefit when treating hepatitis C virus infection (HCV) with direct acting antivirals (DAA). As most of the available data were obtained from clinical trials, limited generalizability to the real-world population might exist. This study aimed to investigate the impact of DAA therapy on changes in HRQoL in a real-world setting. HRQoL of 1180 participants of the German Hepatitis C-Registry was assessed by Short-Form 36 (SF-36) questionnaires. Scores at post-treatment weeks 12-24 (FU12/24) were compared to baseline (BL). Changes of ≥2.5 in mental and physical component summary scores (MCS and PCS) were defined as a minimal clinical important difference (MCID). Potential predictors of HRQoL changes were analysed. Overall, a statistically significant increase in HRQoL after DAA therapy was observed, that was robust among various subgroups. However, roughly half of all patients failed to achieve a clinically important improvement in MCS and PCS. Low MCS (p < .001, OR = 0.925) and PCS (p < .001, OR = 0.899) BL levels were identified as predictors for achieving a clinically important improvement. In contrast, presence of fatigue (p = .023, OR = 1.518), increased GPT levels (p = .005, OR = 0.626) and RBV containing therapy regimens (p = .001, OR = 1.692) were associated with a clinically important decline in HRQoL after DAA therapy. In conclusion, DAA treatment is associated with an overall increase of HRQoL in HCV-infected patients. Nevertheless, roughly half of the patients fail to achieve a clinically important improvement. Especially patients with a low HRQoL seem to benefit most from the modern therapeutic options.
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http://dx.doi.org/10.1111/jvh.13546DOI Listing
August 2021

Reply.

Clin Gastroenterol Hepatol 2022 04 31;20(4):e910-e911. Epub 2021 Mar 31.

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

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http://dx.doi.org/10.1016/j.cgh.2021.03.036DOI Listing
April 2022

Freiburg index of post-TIPS survival (FIPS) a valid prognostic score in patients with cirrhosis but also an advisor against TIPS?

J Hepatol 2021 08 12;75(2):487-489. Epub 2021 Mar 12.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2021.02.031DOI Listing
August 2021

Significant compartment-specific impact of different RNA extraction methods and PCR assays on the sensitivity of hepatitis E virus detection.

Liver Int 2021 08 22;41(8):1815-1823. Epub 2021 Mar 22.

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

Background: RNA detection in plasma/stool is the gold-standard for diagnosis of hepatitis E virus (HEV) infection. The impact of viral extraction methods on HEV RNA detection is poorly investigated.

Methods: We determined the limit of detection of the RealStar HEV RT-PCR V2.0 Kit (altona Diagnostics, RS) utilizing 3 RNA extraction methods (COBAS AmpliPrep Total Nucleic Acid Isolation Kit, TNAi Roche; MagNA Pure 96 DNA, Viral NA SV Kit, MgP; QIAamp Viral RNA mini Kit Qiagen; VRK) in plasma and stool. The most sensitive method was evaluated in a total of 307 longitudinal samples of patients with HEV infection (acute = 18/chronic = 36) and compared to results with the former diagnostic standard of our centre (TNAi/FastTrack Diagnostic; FTD).

Results: The plasma-LOD was 49, 94 and 329 IU/mL for extraction with MgP, VRK and TNAi respectively. In stool, the LOD was 21 IU/mL, 528 IU/mL and indefinable for extraction with TNAi, VRK and MgP respectively. Utilizing longitudinal patient plasma samples, MgP/RS revealed 56 HEV RNA-positive samples in 158 negative samples as determined by TNAi/FTD. In stool, from 37 HEV negative samples (TNAi/FTD), 15 were positive with TNAi/RS. At end of treatment, 8 out of 27 chronically infected patients were RNA positive with MgP/RS, while classified negative with TNAi/FTD. A relapse occurred in 3 of these patients.

Conclusion: Different methods for RNA extraction and quantification have a significant, compartment-specific impact on the sensitivity of HEV detection. Knowledge about the favourable combinations of extraction and quantification has important implications for diagnosis and patients receiving antiviral therapy.
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http://dx.doi.org/10.1111/liv.14870DOI Listing
August 2021
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