Validation of the simplified Animal Naming Test as primary screening tool for the diagnosis of covert hepatic encephalopathy

Diagnosis of covert hepatic encephalopathy (CHE) is time consuming in clinical practice. Recently, a new diagnostic tool - the simplified Animal Naming Test (S-ANT1) - was presented with promising results in an Italian cohort. The aim of the present study was to validate S-ANT1 in a cohort of cirrhotic patients from a German tertiary referral centre.143 cirrhotic patients and 37 healthy controls were enrolled. Hepatic encephalopathy (HE) grade 1 (HE1) was clinically diagnosed according to the West-Haven Criteria. Critical flicker frequency and Psychometric Hepatic Encephalopathy Score were used to detect minimal HE (MHE). All participants were additionally examined by S-ANT1.58 (40.6%) pati…

Liver transplanted patients with preoperative autoimmune hepatitis and immunological disorders are at increased risk for Post-Transplant Lymphoproliferative Disease (PTLD).

Long term immunosuppression and therapy of acute rejections result in a 20-120-fold increased risk to develop Non Hodgkin lymphoma (NHL). Since immunosuppressive therapy and immunological disorders are major risk factors for the development of NHL in the non-transplant population we aimed to analyze risk factors for PTLD in our cohort of liver transplanted (LT) patients.We analyzed retrospectively 431 patients liver transplanted between 1998 and 2008.PTLD was diagnosed in eleven of 431 patients (2.6%). PTLD, especially late PTLD, was significantly more frequent in patients who received steroids before LT (Kaplan-Meier: p0.001). Moreover PTLD in immunocompromised patients with preoperative s…

Expression and prognostic significance of insulin‑like growth factor-2 receptor in human hepatocellular carcinoma and the influence of transarterial chemoembolization

Hepatocellular carcinoma (HCC) is one of the most common human malignancies, the incidence of which is growing worldwide. The prognosis of HCC is very poor and it is often accompanied by a high rate of recurrence. Conventional chemotherapeutic approaches are largely inefficient. In order to develop novel effective methods for the early detection and prognosis of HCC, novel markers and therapeutic targets are urgently required. The present study focused on the effects of the expression of the tumor suppressor gene insulin‑like growth factor‑2 receptor (IGF2R) on patient survival and tumor recurrence in patients with HCC; this study paid specific attention to the influence of transarterial ch…

Long-term observation of hepatocellular carcinoma recurrence after liver transplantation at a European transplantation centre

BACKGROUND: The recurrence of hepatocellular carcinoma (HCC) is the strongest survival-limiting factor after liver transplantation (LT) in patients with HCC. In the face of donor organ shortage, it is necessary to identify factors associated with HCC recurrence in order to maximize the utility of the available grafts. OBJECTIVE: To study the phenomenon of HCC recurrence after LT at a European transplantation centre over the past 20 years. METHODS: Data from 304 HCC patients who underwent LT were prospectively recorded. Clinical and pathological factors were assessed for their association with recurrence. RESULTS: Fifty-one patients (16.8%) had HCC recurrence after LT. Patients exceeding the…

Cirrhosis risk score of the donor organ predicts early fibrosis progression after liver transplantation.

Background & Aims: Fibrosis progression (FP) after liver transplantation (LT) increases morbidity and mortality. Biomarkers are needed for early prediction of FP. A recipient’s seven-gene cirrhosis risk score (CRS) has been associated with FP, especially in non-transplant cohorts. A broader validation of CRS, including the genotype of the donor-organ and HCV-negative patients is lacking. We therefore analyzed the impact of donor- and recipient-specific genotypes on FP after LT in a large cohort of HCV-positive and -negative patients.Method: Genotyping from liver biopsies (n=201 donors) and peripheral blood (n=442 recipients) was performed. Cirrhosis risk score was correlated with FP at …

DHCR_OST-Cannabis_Alcohol_supplementary_2018-10-30_xyz151015746ed84_3-converted – Supplemental material for Alcohol and Cannabis Consumption Does Not Diminish Cure Rates in a Real-World Cohort of Chronic Hepatitis C Virus Infected Patients on Opioid Substitution Therapy—Data From the German Hepatitis C-Registry (DHC-R)

Supplemental material, DHCR_OST-Cannabis_Alcohol_supplementary_2018-10-30_xyz151015746ed84_3-converted for Alcohol and Cannabis Consumption Does Not Diminish Cure Rates in a Real-World Cohort of Chronic Hepatitis C Virus Infected Patients on Opioid Substitution Therapy—Data From the German Hepatitis C-Registry (DHC-R) by Stefan Christensen, Peter Buggisch, Stefan Mauss, Klaus HW Böker, Tobias Müller, Hartwig Klinker, Tim Zimmermann, Yvonne Serfert, Bernd Weber, Jens Reimer and Heiner Wedemeyer in Substance Abuse: Research and Treatment

Cetuximab-induced skin exanthema: Improvement by a reactive skin therapy

More than 80% of patients treated with cetuximab develop an acneiform follicular skin exanthema. Grade 3 exanthema develops in 9-19% of these cases, bearing the risk of cetuximab dose-reduction or cessation. We retrospectively analysed a cohort of 20 patients treated with cetuximab and an in-house reactive skin protocol upon development of an exanthema. The reactive skin protocol was built up as follows: grade 1 exanthema: topical cleansing syndet (Dermowas®) + topical metronidazole cream (Rosiced®); grade 2 exanthema: grade 1 treatment + oral minocycline 50 mg twice per day; grade 3 exanthema: grade 2 treatment + topical corticoid (Dermatop®) + topical nadifloxacin (Nadixa®). As soon as a …

Clinical significance of detectable and quantifiable HCV RNA at the end of treatment with ledipasvir/sofosbuvir in GT1 patients

Background & aims AASLD/IDSA treatment guidelines for hepatitis C virus (HCV) infection state that testing for quantitative HCV RNA can be considered at the end of antiviral treatment (EOT) with interferon-free regimens. However, it remains unclear how to respond to a detectable or even quantifiable HCV RNA result. The aim of this study was to analyse the frequency and predictive value of detectable and quantifiable HCV RNA results at the EOT in patients with HCV genotype 1 infection treated with ledipasvir (LDV) and sofosbuvir (SOF) ± ribavirin (RBV) in a large real-world cohort. Methods A retrospective analysis of the DHC-R (Deutsches Hepatitis C-Register, German Hepatitis C-Registry) coh…

S3-Leitlinie „Prophylaxe, Diagnostik und Therapie der Hepatitis-C-Virus (HCV) -Infektion“ : AWMF-Register-Nr.: 021/012

Das Hepatitis-C-Virus induziert die Expression vaskulärer Adhäsionsmoleküle auf humanen Endothelzellen – ein möglicher Zusammenhang mit der HCV-assoziierten kardiovaskulären Mortalität

Telaprevir drug monitoring during antiviral therapy of hepatitis C graft infection after liver transplantation

Background & Aims Recurrence of hepatitis C virus (HCV) infection after orthotopical liver transplantation (OLT) is common and associated with reduced graft and patient survival. The protease inhibitor telaprevir may enhance virological response rates in patients after OLT in combination with pegylated interferon-alfa and ribavirin. Pharmacokinetic studies have shown significant drug–drug interactions between telaprevir and immunosuppression (IS), but telaprevir pharmacokinetics in OLT patients with IS are unknown. Aim of the present study was to analyse telaprevir plasma concentrations in patients with HCV genotype 1 infection after OLT in comparison to patients without OLT and IS. Methods…

Defer or treat? Reasons for treatment decisions in patients with chronic hepatitis C genotype 1 in the early era of directly acting antiviral agents

Abstract Background In chronic genotype 1 hepatitis C, telaprevir or boceprevir plus peginterferon and ribavirin have become the new standard of care. Aim of this study was to identify factors contributing to the decision whether to defer or treat with the current triple regimens. Methods Prospective assessment of eight parameters on 0-4-point scales by the attending physician at a German tertiary referral centre between 1st September 2011 and 31st December 2012. Results 307 patients were evaluated at least once by one of the 11 hepatologists involved; 267 patients were considered, but only 163 were recommended to receive triple therapy. Multivariate regression analysis revealed that a high…

Interferon- and ribavirin-free therapy with new direct acting antivirals (DAA) for chronic hepatitis C improves vascular endothelial function.

Abstract Introduction Chronic Hepatitis C virus infection (HCV) is associated with extrahepatic manifestations and an increased prevalence in cardiovascular disease. New direct acting antivirals (DAA) have revolutionized HCV treatment with high rates of sustained virological response (SVR). Recently it was demonstrated, that SVR reduces morbidity and overall mortality more than can be solely explained by hepatic effects, suggesting that treatment with DAA also affects cardiovascular disease. The aim of this pilot study was to identify possible underlying mechanisms behind the HCV-associated cardiovascular mortality reported by others. Methods and results 20 HCV patients (10 genotype GT1, 10…

Effects of Smoking on Pegylated Interferon alpha 2a and First Generation Protease Inhibitor-based Antiviral Therapy in Naïve Patients Infected with Hepatitis C Virus Genotype 1.


 
 
 
 
 
 Background & Aims: Smoking has multiple effects on factors influencing hepatitis C and antiviral therapy, including lipid metabolism, fibrosis, platelet count and adherence aspects. The aim of this analysis was to determine the impact of smoking on hepatitis C virus antiviral therapy.
 Methods: Data of two cohorts of an observational multicenter study including therapy-naïve patients infected with genotype 1 hepatitis C virus (HCV) treated with dual antiviral therapy (n=7,796) with pegylated interferon alpha 2a in combination with ribavirin, or triple antiviral therapy (n=1,122) containing telaprevir or boceprevir, were analysed.
 Resu…

Early Steroid-Free Immunosuppression With FK506 After Liver Transplantation: Long-Term Results of a Prospectively Randomized Double-Blinded Trial

Background. The aim of this prospective, randomized, double-blinded, placebo-controlled single center study was to evaluate an early steroid-free immunosuppression in liver transplant patients. Methods. From March 2000 to October 2004, 110 patients were included. All patients received tacrolimus and steroids during the first 2 weeks after orthotopic liver transplantation (OLT). Thereafter, patients in the steroid group (n=54) received steroids and the remaining 56 a placebo. After 6 months, the immunosuppression for all was steroid free. Thirty patients were hepatitis C positive. Five years after inclusion, patient survival, organ survival, steroid side effects, and recirrhosis in hepatitis…

Risk Factors in Patients With Rapid Recurrent Hepatitis C Virus–Related Cirrhosis Within 1 Year After Liver Transplantation

Abstract Background Recurrent cirrhosis (RC) due to pretransplant underlying disease leads to organ failure and subsequent death after orthotopic liver transplantation (OLT). RC occurs in up to 30% of patients with recurrent hepatitis C (HCV) within 5 years after OLT. We sought to identify early risk factors for rapid RC within the first year after OLT in HCV-positive patients. Methods Among 404 liver transplanted patients at the University of Mainz between 1998 and 2008, 90 were HCV-RNA positive. To identify predictive factors for rapid RC, we compared HCV-positive patients with advanced fibrosis stages within 1 year after OLT ( n = 13) with these without RC at 5 years after OLT ( n = 23).…

Efficacy and safety of direct-acting antiviral therapy in previous hard-to-treat patients with recurrent hepatitis C virus infection after liver transplantation: a real-world cohort.

Sebastian Bernuth,1 Daniel Grimm,1 Johanna Vollmar,1 Felix Darstein,1 Jens Mittler,2 Michael Heise,2 Maria Hoppe-Lotichius,2 Peter R Galle,1 Hauke Lang,2 Tim Zimmermann1 1First Department of Internal Medicine, Transplant Hepatology, 2General-, Abdominal- and Transplant- Surgery, University Medical Center, Johannes Gutenberg University, Mainz, Germany Background: Recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) has been a frequent and relevant problem in the past two decades. This analysis evaluated the efficacy and safety of new interferon (IFN)-free direct-acting antiviral (DAA) therapies in a large real-world cohort of HCV patients after LT.Methods: We retrospe…

Urinary ethyl glucuronide (uEtG) as a marker for alcohol consumption in liver transplant candidates: a real-world cohort

 In order to reduce alcohol relapse after liver transplantation (LT), the German national guidelines for waiting-list maintenance and organ allocation demand a minimum 6-month period of alcohol abstinence pre-LT, confirmed by measuring urinary ethyl glucuronide (uEtG). Between January 2015 and June 2016, uEtG was measured at least once in 339 cirrhotic patients with an indication for LT at the University Medical Center Mainz. uEtG was measured with an enzyme-linked immunosorbent assay (ELISA) screening test (cutoff value: 500 µg/L). For uEtG values ≥ 500 µg/L, liquid chromatography-mass spectrometry (LC-MS/MS) was performed as a confirmatory assay. Data were collected prospectively in a tra…

Downregulation of organic cation transporter 1 (SLC22A1) is associated with tumor progression and reduced patient survival in human cholangiocellular carcinoma

Cholangiocellular carcinoma (CCA) is a primary hepatic malignancy derived from cholangiocytes. The prognosis for CCA patients is very poor and conventional chemotherapy has been proven ineffective in improving long‑term patient survival rates. Organic cation transporters (OCTs) mediate the transport of a broad spectrum of endogenous substrates and the detoxification of xenobiotics. Moreover, OCTs are considered responsible for the responsiveness towards platinum‑based chemotherapies. Currently, there are no data available regarding the role of OCTs in CCA. Therefore, the aim of this study was to investigate the expression of OCT1 and OCT3 in CCA and the corresponding non-neoplastic tumor‑su…

Cloning and characterization of the promoter of Hugl-2, the human homologue of Drosophila lethal giant larvae (lgl) polarity gene.

The human lgl gene, Hugl-2 (llgl2, Lgl2), codes for a cytoskeletal protein involved in regulating cell polarity. Here, we report the identification and functional characterization of the promoter region ( approximately 1.2kb) of the Hugl-2 gene. Luciferase expression assays show a high basal Hugl-2 promoter activity in different cell lines and primary human hepatocytes. Truncations of the promoter identified a GC-rich region important for this activity. Alignment of human and mouse genomic sequences demonstrate that this is an evolutionary conserved region fcontaining putative binding sites for several transcription factors including Elk-1 and Sp-1. Mithramycin A reduces Hugl-2 expression i…

Alcohol and Cannabis Consumption Does Not Diminish Cure Rates in a Real-World Cohort of Chronic Hepatitis C Virus Infected Patients on Opioid Substitution Therapy-Data From the German Hepatitis C-Registry (DHC-R).

Background: The importance of alcohol and cannabis consumption for the effectiveness of treatment of chronic hepatitis C virus (HCV) infection with direct acting antivirals (DAAs) in people on opioid substitution therapy (OST) has not been investigated in detail. Methods: We investigated sustained virological response (SVR) rates and proportion of lost to follow-up (LTFU) between OST (n = 739) and non-OST patients (n = 7008) in the German Hepatitis C-Registry (Deutsches Hepatitis C-Register, DHC-R), which is a national multicenter prospective non-interventional real-world registry. Non-OST patients comprised patients with former/current drug use (non-OST/DU; n = 1500) and patients never con…

The recipient CYP2D6 allele 4-associated poor metabolizer status correlates with an early fibrosis development after liver transplantation

Summary CYP2D6 is part of the cytochrome P450 system, which catalyzes biotransformation of endogenous substrates and xenobiotics. Approximately 10% of the Caucasian population has two null alleles, resulting in a poor metabolizer (PM) status. Mostly, allele four (CYP2D6*4) is responsible for the PM status, which is suspected to be associated with an accelerated fibrosis progression (FP). The aim of the present study was to analyze the role of the CYP2D6*4 genotype for FP after liver transplantation (LT). Genotypes were determined in liver biopsies (donor) and peripheral blood (recipient) by fluorescence resonance energy transfer. Data were correlated with clinical variables and risk factors…

Evolution of HCV patient characteristics and DAA regimens in the German Hepatitis C Registry (DHC-R) in 2014 and 2015

 The urgent need in HCV-infected patients with liver disease mandated the rapid implementation of IFN-free DAA combination therapies following their regulatory approval in 2014 and 2015 without full knowledge of the optimal combinations and regimens. Investigating the evolution of the DAA utilization patterns and treatment outcomes could provide learnings for future situations. This was an analysis of a prospective observational database from the German Hepatitis C Registry (DHC-R) covering a period from May 2014 to September 2015. Adult patients had evidence of chronic HCV GT1 or GT4 infection and were treated with an IFN-free combination regimen of simeprevir (SMV) + sofosbuvir (SOF) or o…

Antiviral triple therapy with boceprevir in a chronic hepatitis C haemodialysis patient awaiting kidney re-transplantation

Alterations in lipid, carbohydrate and iron metabolism in patients with non-alcoholic steatohepatitis (NASH) and metabolic syndrome

NASH (non-alcoholic steatohepatitis) is considered the hepatic manifestation of the metabolic syndrome (MS). We aimed to analyze lipid, carbohydrate, and iron metabolism in NASH.37 patients with MS (17 M/20 F, 51+/-15 years), elevated transaminases; 25 patients had histologically proven NASH (NAS score≥5), 12 patients had toxic background (nonNASH). 37 age, sex, BMI-matched healthy controls. Lipid variables, LDL-subfractions, iron, ferritin, transferrin (T), transferrin saturation (TS), and hepcidin (H) were measured in patients/controls. Oral glucose tolerance tests were performed.NASH patients with steatosis gr. 2 and 3 (33% hepatic fat) had higher sd-LDL (mg/dl) concentrations than patie…

Real-world experience with the all-oral, interferon-free regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir for the treatment of chronic hepatitis C virus infection in the German Hepatitis C Registry.

Summary Real-world studies are relevant to complement clinical trials on novel antiviral therapies against chronic hepatitis C; however, clinical practice data are currently limited. This study investigated effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r)±dasabuvir (DSV)±ribavirin (RBV) for treatment of HCV genotype (GT) 1 and GT4 infection in a large real-world cohort. The German Hepatitis C Registry is an observational cohort study prospectively collecting clinical practice data on direct-acting antiviral therapies. Patients with GT1/4 infection treated with OBV/PTV/r±DSV±RBV were analysed. Effectiveness was assessed by sustained virologic response in 558 patients…

Predictive factors for sustained virological response after treatment with pegylated interferon α-2a and ribavirin in patients infected with HCV genotypes 2 and 3.

BackgroundPrevious trials have often defined genotype 2 and 3 patients as an "easy to treat" group and guidelines recommend similar management.AimsThe present study looks for differences between the two genotypes and analyzes predictive factors for SVR.MethodsProspective, community-based cohort study involving 421 physicians throughout Germany. The analysis includes 2,347 patients with untreated chronic HCV genotype 2 (n = 391) and 3 (n = 1,956) infection treated with PEG-IFN α-2a plus ribavirin between August 2007 and July 2012.ResultsWhen compared with genotype 2 patients, those with genotype 3 were younger, had a shorter duration of infection, lower values of total cholesterol, LDL chole…

Tacrolimus effects and side effects after liver transplantation: is there a difference between immediate and extended release?

Abstract Background Immunosuppressive therapy after orthotopic liver transplantation (OLT) requires a high degree of patient compliance to guarantee safety and avoid side effects. In 2007, prolonged-release tacrolimus was launched in Europe to improve compliance. In this prospective observational crossover single-center trial, we analyzed effects and side effects of prolonged-release tacrolimus in OLT patients. Methods LT patients at our center were included if they were older than l8 years of age, had had the procedure at least 6 months prior, and were outpatients currently on twice-daily tacrolimus. Patients were observed for 6 months before switching to once-daily tacrolimus. Patient his…

Nachweis hepatischer Mikrometastasen

Colorectal cancer is one of the three most frequent malignancies in humans. Survival is mainly determined by local recurrence, lymphatic and hematogenous dissemination. Primary liver resection for metastases is possible in ~20-25% of patients with hepatic metastases and results in a 50% recurrence rate within 23 months. The five-year survival without treatment in patients with UICC stage IV is only 5%, the mean survival 6-9 months. As a result of promising developments in chemotherapy and targeted therapies in the last decade, the mean survival rate has significantly improved to over more than two years. Furthermore, the use of polychemotherapy in combination with anti-angiogenic and anti-p…

285 DOWNREGULATION OF ORGANIC CATION TRANSPORTERS OCT1 (SLC22A1) AND OCT3 (SLC22A3) IN HUMAN HEPATOCELLULAR CARCINOMA AND THEIR PROGNOSTIC SIGNIFICANCE

Background Organic cation transporters (OCT) are responsible for the uptake and intracellular inactivation of a broad spectrum of endogenous substrates and detoxification of xenobiotics and chemotherapeutics. The transporters became pharmaceutically interesting, because OCTs are determinants of the cytotoxicity of platin derivates and the transport activity has been shown to correlate with the sensitivity of tumors towards tyrosine kinase inhibitors. No data exist about the relevance of OCTs in hepatocellular carcinoma (HCC).

MRI findings and genotype analysis in patients with childhood onset growth hormone deficiency--correlation with severity of hypopituitarism.

Aim: To evaluate the relationship between pituitary size, PIT1 and PROP1 genotype, and the severity of childhood onset growth hormone deficiency (coGHD). Patients: Forty-four patients with coGHD (34 M; 9.7 ± 4.1 years): severe isolated (SI) GHD (n = 14); partial isolated (PI) GHD (n = 13); multiple pituitary hormone deficiencies (MPHD) (n=17). Results: Pituitary abnormalities were found in 7/14 patients with SIGHD (50%), 16/17 patients with MPHD (94.1%), and no patient with PIGHD. Mean pituitary height (PHT SDS) was significantly lower in MPHD than in SIGHD and PIGHD. Pituitary height SDS and pituitary volume (PV) SDS correlated with IGF-I SDS and stimulated GH peaks in the SIGHD and MPHD g…

Alterations in Lipid and Carbohydrate Metabolism in Patients with Classic Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

<i>Background:</i> Classic 21-hydroxylase deficiency (21HD) presents some traits of the metabolic syndrome. <i>Aim:</i> To characterize discrete alterations of lipid and carbohydrate metabolism in children and young adults with classic 21HD, which could predict early atherogenesis. <i>Patients and Methods:</i> Twenty-seven Caucasian patients with classic 21HD (4–31 years); 27 sex-, age- and BMI-matched controls. Clinical parameters, hormonal status and genotype were assessed in all patients. Lipid parameters, including relative (%) and absolute (mg/dl) small-dense low-density lipoproteins subfractions (sd-LDL) were measured in patients and controls. Oral …

IMPACT OF DIRECT-ACTING ANTIVIRAL THERAPY ON THE NEED FOR LIVER TRANSPLANTATION RELATED TO HEPATITIS C IN GERMANY

Metabolic syndrome and its association with fatty liver disease after orthotopic liver transplantation

The metabolic syndrome (MetS) might contribute to morbidity after orthotopic liver transplantation (OLT). For this reason, we searched for MetS-associated risk factors and analyzed the link with nonalcoholic fatty liver disease (NAFLD) in OLT recipients. De novo MetS affected 32.9% of our cohort (n = 170) within 2 years after OLT. Multivariate analysis identified glycosylated hemoglobin (HbA1c) levels ≥5% [odds ratio (OR) = 3.5; 95% confidence interval (CI) = 1.56-8.13, P = 0.003], diabetes mellitus (OR = 4.31, CI = 1.69-10.99, P = 0.002), and arterial hypertension (OR = 4.59, CI = 1.46-14.49, P = 0.009) as independent risk factors for de novo MetS. MetS incidence correlated with steroid do…

Mo1658 EVALUATION OF BOWEL CLEANSING EFFICACY IN HOSPITALIZED PATIENT POPULATION USING THE PURE-VU SYSTEM

Extrahepatische Malignome nach Lebertransplantation wegen Primär Sklerosierender Cholangitis – eine multizentrische Langzeit-Beobachtungsstudie

Ablation of c-FLIP in hepatocytes enhances death-receptor mediated apoptosis and toxic liver injury in vivo

Background & Aims Apoptosis is crucially involved in acute and chronic liver injury, including viral, cholestatic, toxic, and metabolic liver disease. Additionally, dysregulation of apoptosis signaling pathways has been implicated in hepatocarcinogenesis. The most prominent members of the apoptosis-mediating tumor necrosis factor receptor superfamily are the TNF-R1 (CD120a) and the CD95 (Apo-1/Fas) receptor. Although extensively studied, the intracellular signaling events in hepatocytes are only incompletely understood. Methods To examine the role of the caspase-8 homolog cellular FLICE-inhibitory protein (c-FLIP) in liver injury, we generated mice with hepatocyte specific deletion of c-FLI…

Increased hepatic fibrosis and JNK2-dependent liver injury in mice exhibiting hepatocyte-specific deletion of cFLIP.

Chronic liver disease promotes hepatocellular injury involving apoptosis and triggers compensatory regeneration that leads to the activation of quiescent stellate cells in the liver. The deposition of extracellular matrix from activated myofibroblasts promotes hepatic fibrosis and the progression to cirrhosis with deleterious effects on liver physiology. The role of apoptosis signaling pathways in the development of fibrosis remains undefined. The aim of the current study was to determine the involvement of the caspase-8 homologue cellular FLICE-inhibitory protein (cFLIP) during the initiation and progression of fibrosis. Liver injury and fibrosis from carbon tetrachloride (CCl4) and thioa…

Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance

Abstract Background Organic cation transporters (OCT) are responsible for the uptake and intracellular inactivation of a broad spectrum of endogenous substrates and detoxification of xenobiotics and chemotherapeutics. The transporters became pharmaceutically interesting, because OCTs are determinants of the cytotoxicity of platin derivates and the transport activity has been shown to correlate with the sensitivity of tumors towards tyrosine kinase inhibitors. No data exist about the relevance of OCTs in hepatocellular carcinoma (HCC). Methods OCT1 (SLC22A1) and OCT3 (SLC22A3) mRNA expression was measured in primary human HCC and corresponding non neoplastic tumor surrounding tissue (TST) by…

Progression of transthyretin (TTR) amyloidosis in donors and recipients after domino liver transplantation-a prospective single-center cohort study

Liver transplantation (LT) is the first-line therapy in patients with transthyretin (TTR) amyloidosis and progressive familial amyloid polyneuropathy (FAP). Explanted organs from these patients can be used for domino liver transplantation (DLT). After DLT, de novo amyloidosis may develop in domino recipients (DR). Data were collected prospectively in a transplant database. Electroneurography by nerve conduction velocity (NCV), quantitative sensory testing, heart rate variability (HRV), sympathetic skin response, orthostatic reaction (tilt table test), transthoracic echocardiography, cardiac MRI and organ biopsy results were evaluated. The cohort included 24 FAP- (11 Val30Met, 13 nonVal30Met…

Managing hepatitis C in liver transplant patients with recurrent infection

Tim Zimmermann1, Gerd Otto2, Marcus Schuchmann11Department of Internal Medicine, 2Transplantation Surgery, University of Mainz, GermanyAbstract: Hepatitis C virus (HCV) reinfection after liver transplantation (LT) and recurrent hepatitis C often lead to recurrent cirrhosis (RC). RC is one of the most frequent complications resulting in organ failure and early death after LT in HCV-positive patients with reported 5-year rates from 20% to 40%. As HCV-cirrhosis is one of the leading indications for LT, the therapeutic management is a central issue. To date, the best available therapy is a combination of pegylated interferon + ribavirin in patients with established recurrent hepatitis C proven …

Early changes in dynamic biomarkers of liver fibrosis in hepatitis C virus-infected patients treated with sofosbuvir

Abstract Background Chronic hepatitis C is a major cause of liver-associated mortality caused by decompensated cirrhosis and hepatocellular carcinoma. With the approval of sofosbuvir, therapeutic efficacy has markedly increased. Early changes in non-invasive biomarkers of liver fibrosis under effective antiviral therapy are widely unknown. Aim To evaluate early changes of fibrosis markers determined by enhanced liver fibrosis (ELF) scores and liver stiffness measurement (FibroScan®) in patients treated with sofosbuvir. Methods A total of 32 hepatitis C patients treated prospectively with sofosbuvir were included. The ELF-panel and FibroScan measurements were performed at baseline, week 4, e…

Hepatocellular carcinoma in Child's A cirrhosis: a retrospective analysis of matched pairs following liver transplantation vs. liver resection according to the intention-to-treat principle.

This is the first matched pair analysis on the puzzling clinical problem of whether to perform liver transplantation (LT) or liver resection (LR) for Child's A hepatocellular carcinoma (HCC) patients. A total of 201 patients diagnosed with HCC and Child's A liver cirrhosis were treated with LT transarterial chemoembolization (TACE) or LR between 1998 and 2012. To achieve the most accurate study design, two groups of 57 patients were matched retrospectively according to their tumor characteristics detected by the initial computerized tomography (CT) scan. Sixteen of 57 LT candidates were not transplanted due to tumor progress during pre-treatment (TACE). Nevertheless, the retrospective analy…

The role of death effector domain (DED)-containing proteins in acute oxidative cell injury in hepatocytes

Abstract Apoptosis is a mechanism that regulates hepatic tissue homeostasis and contributes to both acute and chronic injury in liver disease. The apoptotic signaling cascade involves activation of the death-inducing signaling complex (DISC) and subsequent recruitment of proteins containing death effector domains (DED), which regulate downstream effector molecules. Prominent among these are the Fas-associated death domain (FADD) and the cellular caspase 8-like inhibitory protein (cFLIP), and alterations in these proteins can lead to severe disruption of physiological processes, including acute liver failure or hepatocellular carcinoma. Their role in cell signaling events independent of the …

Supplemental material for Long-term observation of hepatocellular carcinoma recurrence after liver transplantation at a European transplantation centre

Supplemental Material for Long-term observation of hepatocellular carcinoma recurrence after liver transplantation at a European transplantation centre by Friedrich Foerster, Maria Hoppe-Lotichius, Johanna Vollmar, Jens U Marquardt, Arndt Weinmann, Marcus-Alexander Wörns, Gerd Otto, Tim Zimmermann and Peter R Galle in United European Gastroenterology Journal

Hepatische Manifestation eines Makrophagen-Aktivierungs-Syndroms (MAS)

Hintergrund Leberwerterhohungen gehoren zu den haufigsten pathologischen Laborbefunden in Deutschland. Haufige Ursachen einer Leberwerterhohung stellen neben einer nutritiv- und medikamentos-toxischen Schadigung, vor allem bei jungeren Patienten, virale oder autoimmune Ursachen dar. Das MAS kann sich ahnlich einer viralen Infektionserkrankung mit Fieber, Hepatosplenomegalie und Panzytopenie manifestieren und ist mit einer hohen Mortalitat assoziiert. Zugrunde liegt eine verstarkte Aktivierung der Makrophagen mit gesteigerter Zytokinausschuttung, was zu Endorganschaden mit Multiorganversagen fuhren kann. Neben genetischen Ursachen findet sich ein MAS haufig im Zusammenhang mit Infekten und r…

Diagnostik und Management des Rezidivs der Primär Sklerosierenden Cholangitis nach Lebertransplantation – eine multizentrische Langzeit-Beobachtungsstudie der deutschen PSC-Studiengruppe

Loss of organic cation transporter 3 (Oct3) leads to enhanced proliferation and hepatocarcinogenesis

// Johanna Vollmar 1 , Anja Lautem 2 , Ellen Closs 3 , Detlef Schuppan 4 , Yong Ook Kim 4 , Daniel Grimm 1 , Jens U. Marquardt 1 , Peter Fuchs 1 , Beate K. Straub 5 , Arno Schad 5 , Dirk Grundemann 6 , Jorn M. Schattenberg 1 , Nadine Gehrke 1 , Marcus A. Worns 1 , Jan Baumgart 7 , Peter R. Galle 1 and Tim Zimmermann 1 1 Department of Internal Medicine, Gastroenterology and Hepatology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany 2 Department of Hepatobiliary and Transplantation Surgery, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany 3 Department of Pharmacology, University Medical Center, Johannes Gutenberg-University Mainz, …

Direct-acting antiviral treatment of chronic HCV-infected patients on opioid substitution therapy: Still a concern in clinical practice?

BACKGROUND AND AIMS There is limited real-world information on the effectiveness of antiviral treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals (DAA) in people on opioid substitution therapy (OST). This study compared sustained virological response (SVR) rates and proportion of lost to follow-up (LTFU) between OST and non-OST patients in the German Hepatitis C-Registry (DHC-R). DESIGN National multi-centre prospective real-world registry (German Hepatitis C-Registry, DHC-R). Non-OST patients comprised patients with former/current drug use (non-OST/DU) and patients never consuming drugs (non-OST/NDU). SETTING A total of 254 medical centres in Germany, inclu…

Clinical Predictors for Poor Quality of Life in Patients With Covert Hepatic Encephalopathy.

Background Current EASL/AASLD guidelines recommend treatment of covert hepatic encephalopathy (HE) only in symptomatic patients, for example, in those with impaired quality of life or with affected driving abilities. Goals Because testing for impaired quality of life is time consuming, the aim of the present study was to identify simple clinical predictors for poor quality of life in patients with covert HE (CHE). Study In total, 139 cirrhotic in- and outpatients without a history of overt hepatic encephalopathy were enrolled. Diagnosis of HE grade 1 (HE1) was diagnosed clinically according to the West-Haven Criteria. Critical flicker frequency and the Psychometric Hepatic Encephalopathy Sc…

Die Leberfunktion vor Lebertransplantation bestimmt das Überleben nach Lebertransplantation beim hepatozellulären Karzinom

Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors

Apoptosis signaling is involved in both physiological tissue homeostasis and acute and chronic diseases. The role of regulatory apoptosis signaling molecules and their organ-specific functions are less defined. Therefore, we investigated the loss of the anti-apoptotic cellular FLICE-inhibitory protein (cFLIP) and the mechanisms of the resulting lethal organ failure in vivo using inducible knockout mice. These were generated by crossing floxed cFLIP mice to a tamoxifen inducible Rosa26-creERT2 mouse strain. Death following global loss of cFLIP resulted from liver failure, accumulation of M1-polarized macrophages and accompanying hepatic cell death and inflammation. Apoptosis was also promine…

Efficacy of an escalating dose regimen of pegylated interferon ?-2a plus ribavirin in the early phase of HCV reinfection after liver transplantation

We evaluated the safety and efficacy of an escalating dose regimen of pegylated interferon alpha-2a (PEG-IFN(alpha-2a)) and ribavirin in the early phase of recurrent hepatitis C after orthotopic liver transplantation (OLT). In this prospective study, 26 patients transplanted for hepatitis C virus cirrhosis with recurrent hepatitis C were treated 3.4 +/- 3.6 months after OLT and compared with an untreated historical control. PEG-IFN(alpha-2a) was initiated as monotherapy, following stepwise dose escalation up to 180 mug/week and the addition of ribavirin up to 1200 mg/day or maximally tolerated doses for 48 weeks. In the intent-to-treat analysis, 38% showed an early virological response (EVR…

Sarcopenia as prognostic factor for survival after orthotopic liver transplantation

Background and aim Body composition has emerged as a prognostic factor for end-stage liver disease. We therefore investigated muscle mass, body fat and other clinical-pathological variables as predictors of posttransplant survival. Methods A total of 368 patients, who underwent orthotopic liver transplantation (OLT) at our institution, were assessed prior to OLT and followed for a median of 9.0 years (range 2.0-10.0 years) after OLT. Psoas, erector spinae and the combined paraspinal muscle area, as well as the corresponding indices normalized by body-height squared, were quantified by a lumbar (L3) cross-sectional computed tomography. In addition, absolute body fat and bone density were est…

Deletion of organic cation transporter Oct3 promotes hepatic fibrosis via upregulation of TGFβ

Organic cation transporters (OCT) are responsible for the intracellular uptake and detoxification of a broad spectrum of endogenous and exogenous substrates. OCTs are downregulated in cholestasis, fibrosis, and hepatocellular carcinoma, but the underlying molecular mechanisms and downstream effects of OCT deletion are unknown. Oct3-knockout ( Oct3−/−; FVB.Slc22a3tm10pb) and wild-type (WT; FVB) mice were subject to escalating doses of carbon tetrachloride (CCl4) or thioacetamide (TAA) for 6 wk to induce advanced parenchymal liver fibrosis. Secondary biliary fibrosis was generated by bile duct ligation. Liver fibrosis was assessed by hydroxyproline determination, quantitative Sirius red morp…

Prospective evaluation of the impact of covert hepatic encephalopathy on quality of life and sleep in cirrhotic patients

BACKGROUND Minimal hepatic encephalopathy (HE) and HE grade 1 (HE1) according to the West Haven criteria have recently been grouped as one entity named-covert HE- (CHE). Data regarding the impact of CHE on health-related quality of life (HRQoL) and sleep quality are controversial. AIM First, to determine whether CHE affects HRQoL and sleep quality of cirrhotic patients and second, whether minimal HE (MHE) and HE1 affect HRQoL and sleep quality to a comparable extent. METHODS A total of 145 consecutive cirrhotic patients were enrolled. HE1 was diagnosed clinically according to the West Haven criteria. Critical flicker frequency and the Psychometric Hepatic Encephalopathy Score were used to d…

Diagnostische Wertigkeit der Endoskopie zur Erkennung einer GvHD im oberen Gastrointestinaltrakt

Functional inhibition of Oct leads to HNF4α upregulation

Organic cation transporters (human, OCT; mouse, Oct) are responsible for the intracellular uptake and detoxification of a broad spectrum of endogenous and exogenous substrates. The OCT1 gene SLC22A1 (human; mouse, Scl22a1) is transactivated by hepatocyte nuclear factor 4α (human, HNF4α; mouse, Hnf4α). HNF4α is a master regulator of hepatocyte differentiation and is frequently associated with hepatocellular carcinoma (HCC). In addition, the downregulation of HNF4α is associated with enhanced fibrogenesis. Our recent study revealed that hepatocarcinogenesis and fibrosis were enhanced with the loss of Oct3 (gene, Slc22a3). Notably, differences in Hnf4α expression, and in cholestasis and fibros…

Alloimmune hemolytic anemia after liver transplantation from an ABO-identical and Rh-nonidentical donor in a patient with postpartum Budd-Chiari syndrome

Ten Years of Simultaneous Pancreas-Kidney Transplantation: A Retrospective Single-Center Analysis of Prospectively Obtained Data

Simultaneous pancreas-kidney transplantation (SPK) is a standardized and life-saving procedure for a patient suffering from both insulin-dependent diabetes mellitus type 1 (IDDM 1) and end-stage diabetic nephropathy. To expand the donor pool and to determine the influence of the preprocurement pancreas suitability scoring system (P-PASS) on pancreas graft survival we retrospectively analyzed our data on SPK.From 1999 to 2010 we performed 55 SPKs, using systemic-enteric drainage as surgical approach. The immunosuppressive therapy was induced with basiliximab; maintenance therapy was based on tacrolimus, mycophenolate mofetil, and steroids. Data were prospectively obtained, analyzed, and corr…