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Hadem J.,Hepatology and Endocrinology | Beutel G.,Hannover Medical School
Blood Purification | Year: 2013

Background: Accumulation of middle molecules is thought to have adverse effects in patients with acute kidney injury (AKI). Elimination of middle molecules by non-convective means, i.e. hemodialysis, remains difficult. The aim of the study was to investigate the removal characteristics of a new high permeability membrane in AKI patients undergoing extended dialysis (ED). Patients and Methods: We performed a prospective, crossover study comparing the EMiC2 dialyzer (1.8 m2, FMC, Germany) and AV 1000S (1.8 m 2, FMC) in 11 critically ill patients with AKI. β2- Microglobulin, cystatin c, creatinine, and urea were measured before and after 0.5, 5.0 and 10 h of ED. Serum reduction ratios, dialyzer clearances, and mass in the total collected dialysate were determined. Results: Dialyzer clearance of β2-microglobulin (EMiC2: 52 ± 1.7 ml/min, AV 1000S: 41.7 ± 1.5 ml/min, p = 0.0002) and cystatin c (EMiC2: 47.2 ± 1.2 ml/min, AV 1000S: 34.2 ± 2.3 ml/min, p < 0.0001) was markedly different, as was the reduction of serum levels of β2- microglobulin (EMiC2: 54.3 ± 3.6%, AV 1000S: 39.1 ± 4.5%, p = 0.025) and cystatin c (EMiC2: 38.9 ± 2.6%, AV 1000S: 28.0 ± 3.9%, p = 0.043). Additionally, we observed a higher total amount of these substances in the collected dialysate. There was no significant difference in the total amount of albumin eliminated per treatment. Conclusion: The new EMiC2 dialyzer enhances removal of middle molecules without an increase in albumin loss. The clinical relevance of this finding needs to be determined. Copyright © 2012 S. Karger AG, Basel.


Kneser J.,Hepatology and Endocrinology | Lichtinghagen R.,Medicine Institute for Clinical Chemistry | Kielstein J.T.,Hannover Medical School
Clinical Nephrology | Year: 2013

High-fux hemodialysis is the extracorporeal treatment of choice for various life threatening intoxications. Most published reports support the use of hemoperfusion in the context of severe theophylline poisoning, but the technique is limited by its sig-nifcant side-effects. We present a potentially life threatening theophylline overdose treated with hemodialysis in a pregnant patient. For the frst time the amount of theophylline removed was measured in the total collected spent dialysate, after a 3.75-hour hemodialy-sis and an 8-hour extended dialysis. ©2013 Dustri-Verlag Dr. K. Feistle.


Singh A.K.,Hepatology and Endocrinology | Liu Y.,Hepatology and Endocrinology | Riederer B.,Hepatology and Endocrinology | Engelhardt R.,Hepatology and Endocrinology | And 3 more authors.
Journal of Physiology | Year: 2013

The duodenal villus brush border membrane expresses several ion transporters and/or channels, including the solute carrier 26 anion transporters Slc26a3 (DRA) and Slc26a6 (PAT-1), the Na+/H+ exchanger isoform 3 (NHE3), as well as the anion channels cystic fibrosis transmembrane conductance regulator (CFTR) and Slc26a9. Using genetically engineered mouse models lacking Scl26a3, Slc26a6, Slc26a9 or Slc9a3 (NHE3), the study was carried out to assess the role of these transporters in mediating the protective duodenal bicarbonate secretory response (DBS-R) to luminal acid; and to compare it to their role in DBS-R elicited by the adenylyl cyclase agonist forskolin. While basal DBS was reduced in the absence of any of the three Slc26 isoforms, the DBS-R to forskolin was not altered. In contrast, the DBS-R to a 5 min exposure to luminal acid (pH 2.5) was strongly reduced in the absence of Slc26a3 or Slc26a9, but not Slc26a6. CFTR inhibitor [CFTR(Inh)-172] reduced the first phase of the acid-induced DBS-R, while NHE3 inhibition (or knockout) abolished the sustained phase of the DBS-R. Luminal acid exposure resulted in the activation of multiple intracellular signalling pathways, including SPAK, AKT and p38 phosphorylation. It induced a biphasic trafficking of NHE3, first rapidly into the brush border membrane, followed by endocytosis in the later stage. We conclude that the long-lasting DBS-R to luminal acid exposure activates multiple duodenocyte signalling pathways and involves changes in trafficking and/or activity of CFTR, Slc26 isoforms Slc26a3 and Slc26a9, and NHE3. © 2013 The Physiological Society.


Wedemeyer H.,Hepatology and Endocrinology | Yurdaydin C.,Ankara University | Dalekos G.N.,Technological Educational Institute of Larissa | Erhardt A.,Heinrich Heine University Düsseldorf | And 10 more authors.
New England Journal of Medicine | Year: 2011

Background: Chronic infection with hepatitis B virus and hepatitis delta virus (HDV) results in the most severe form of viral hepatitis. There is no currently approved treatment. We investigated the safety and efficacy of 48 weeks of treatment with peginterferon alfa-2a plus adefovir dipivoxil, peginterferon alfa-2a alone, and adefovir dipivoxil alone. Methods: We conducted a randomized trial in which 31 patients with HDV infection received treatment with 180 μg of peginterferon alfa-2a weekly plus 10 mg of adefovir daily, 29 received 180 μg of peginterferon alfa-2a weekly plus placebo, and 30 received 10 mg of adefovir alone weekly for 48 weeks. Follow-up was conducted for an additional 24 weeks. Efficacy end points included clearance of HDV RNA, normalization of alanine aminotransferase levels, and a decline in levels of hepatitis B surface antigen (HBsAg). Results: The primary end point - normalization of alanine aminotransferase levels and clearance of HDV RNA at week 48 - was achieved in two patients in the group receiving peginterferon alfa-2a plus adefovir and two patients in the group receiving peginterferon alfa-2a plus placebo but in none of the patients in the group receiving adefovir alone. At week 48, the test for HDV RNA was negative in 23% of patients in the first group, 24% of patients in the second, and none of those in the third (P = 0.006 for the comparison of the first and third groups; P = 0.004 for the comparison of the second and third). The efficacy of peginterferon alfa-2a was sustained for 24 weeks after treatment, with 28% of the patients receiving peginterferon alfa-2a plus adefovir or peginterferon alfa-2a alone having negative results on HDV-RNA tests; none of the patients receiving adefovir alone had negative results. A decline in HBsAg levels of more than 1 log10 IU per milliliter from baseline to week 48 was observed in 10 patients in the first group, 2 in the second, and none in the third (P<0.001 for the comparison of the first and third groups and P = 0.01 for the comparison of the first and second). Conclusions: Treatment with peginterferon alfa-2a for 48 weeks, with or without adefovir, resulted in sustained HDV RNA clearance in about one quarter of patients with HDV infection. (Funded by Hep-Net [the German Network of Excellence on Viral Hepatitis] and others; Current Controlled Trials number, ISRCTN83587695). Copyright © 2011 Massachusetts Medical Society. All rights reserved.


Malek N.P.,University Hospital of Tuebingen | Schmidt S.,Hepatology and Endocrinology | Huber P.,Hepatology and Endocrinology | Manns M.P.,Hepatology and Endocrinology | Greten T.F.,U.S. National Institutes of Health
Deutsches Arzteblatt International | Year: 2014

Background: The incidence of hepatocellular carcinoma (HCC) has continued to rise in recent years. This increase has been attributed to alcohol-induced liver diseases, metabolic syndrome, and the rising number of hepatitis B and C viral infections. Methods: Pertinent publications (2000-2011) were retrieved by a systematic Medline search. In seven different subject areas, 41 key questions were defined; 15 of them were answered on the basis of a primary search. In addition, original-source guidelines that are currently available from around the world were assessed and utilized with the aid of a systematic instrument for the evaluation of guidelines (DELBI). Results: All patients with chronic liver disease should undergo ultrasonography every six months for the early detection of HCC. Measurement of the alphafetoprotein (AFP) concentration is not obligatory, as this test is relatively insensitive when used for early detection. If ultrasonography reveals a mass, a tomographic imaging study with contrast should be obtained; the latter may reveal a characteristic pattern of contrast enhancement that can be accepted as definitive evidence of HCC. Fine-needle biopsy has a sensitivity and specificity of over 90% for the diagnosis of HCC. Any patient in whom HCC has been diagnosed should be referred to a center where potentially curative treatments (surgery, transplantation, local ablation) can be considered. Radiofrequency ablation (RFA) is now performed instead of percutaneous ethanol instillation. For patients with advanced tumors, sorafenib should only be offered to those in Child-Pugh stage A. This drug has been found to prolong mean overall survival from 7.9 to 10.7 months. Conclusion: HCC poses particular diagnostic and therapeutic challenges that are best met with an interdisciplinary management approach.


Anwar S.L.,Institute of Pathology | Anwar S.L.,Gadjah Mada University | Krech T.,Institute of Pathology | Hasemeier B.,Institute of Pathology | And 5 more authors.
Journal of Pathology | Year: 2014

The tumour suppressor gene RB1 is frequently silenced in many different types of human cancer, including hepatocellular carcinoma (HCC). However, mutations of the RB1 gene are relatively rare in HCC. A systematic screen for the identification of imprinted genes deregulated in human HCC revealed that RB1 shows imprint abnormalities in a high proportion of primary patient samples. Altogether, 40% of the HCC specimens (16/40) showed hyper- or hypomethylation at the CpG island in intron 2 of the RB1 gene. Re-analysis of publicly available genome-wide DNA methylation data confirmed these findings in two independent HCC cohorts. Loss of correct DNA methylation patterns at the RB1 locus leads to the aberrant expression of an alternative RB1-E2B transcript, as measured by quantitative real-time PCR. Demethylation at the intron 2 CpG island by DNMT1 knock-down or aza-deoxycytidine (DAC) treatment stimulated expression of the RB1-E2B transcript, accompanied by diminished RB1 main transcript expression. No aberrant DNA methylation was found at the RB1 locus in hepatocellular adenoma (HCA, n = 10), focal nodular hyperplasia (FNH, n = 5) and their corresponding adjacent liver tissue specimens. Deregulated RB1 expression due to hyper- or hypomethylation in intron 2 of the RB1 gene is found in tumours without loss of heterozygosity and is associated with a decrease in overall survival (p = 0.032) if caused by hypermethylation of CpG85. This unequivocally demonstrates that loss of imprinting represents an important additional mechanism for RB1 pathway inactivation in human HCC, complementing well-described molecular defects. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


von Hahn T.,Hepatology and Endocrinology
Discovery medicine | Year: 2011

Most novel drugs directed against the hepatitis C virus (HCV) including the recently approved NS3/4A protease inhibitors boceprevir and telaprevir are inhibitors of viral enzymes. Since HCV is an RNA virus with a short and highly variable genome, these direct-acting antivirals (DAAs) are prone to rapidly inducing the emergence of resistant HCV variants. This problem could be mitigated by the development of drugs that target host factors that the virus depends on during the various stages of its replication cycle. An increasing understanding of the molecular interactions between the virus and its host cell has allowed the identification of promising host targets for anti-HCV therapy and several host-targeting agents (HTAs) are currently under development. The most advanced compounds as yet may be inhibitors of cyclophilin A, a host factor known to be critical for viral RNA replication and possible virion assembly or release. One such compound, alisporivir, has demonstrated in vivo efficacy and is now in a phase 3 trial. Several other HTAs with very different host targets are further upstream in the development pipeline. This paper reviews promising host targets, their role in the viral replication cycle, and the HTAs that target them.


Anwar S.L.,Institute of Pathology | Krech T.,Institute of Pathology | Hasemeier B.,Institute of Pathology | Schipper E.,Institute of Pathology | And 4 more authors.
PLoS ONE | Year: 2012

Deregulation of imprinted genes is an important molecular mechanism contributing to the development of cancer in humans. However, knowledge about imprinting defects in human hepatocellular carcinoma (HCC), the third leading cause of cancer mortality worldwide, is still limited. Therefore, a systematic meta-analysis of the expression of 223 imprinted loci in human HCC was initiated. This screen revealed that the DLK1-MEG3 locus is frequently deregulated in HCC. Deregulation of DLK1 and MEG3 expression accompanied by extensive aberrations in DNA methylation could be confirmed experimentally in an independent series of human HCC (n = 40) in more than 80% of cases. Loss of methylation at the DLK1-MEG3 locus correlates linearly with global loss of DNA methylation in HCC (r2 = 0.63, p<0.0001). Inhibition of DNMT1 in HCC cells using siRNA led to a reduction in MEG3-DMR methylation and concomitant increase in MEG3 RNA expression. Allele-specific expression analysis identified loss of imprinting in 10 out of 31 informative samples (32%), rendering it one of the most frequent molecular defects in human HCC. In 2 cases unequivocal gain of bi-allelic expression accompanied by substantial loss of methylation at the IG-DMR could be demonstrated. In 8 cases the tumour cells displayed allelic switching by mono-allelic expression of the normally imprinted allele. Allelic switching was accompanied by gains or losses of DNA methylation primarily at IG-DMR1. Analysis of 10 hepatocellular adenomas (HCA) and 5 cases of focal nodular hyperplasia (FNH) confirmed that this epigenetic instability is specifically associated with the process of malignant transformation and not linked to increased proliferation per se. This widespread imprint instability in human HCC has to be considered in order to minimize unwanted side-effects of therapeutic approaches targeting the DNA methylation machinery. It might also serve in the future as predictive biomarker and for monitoring response to epigenetic therapy. © 2012 Anwar et al.


Wedemeyer H.,Hepatology and Endocrinology
Liver International | Year: 2011

More than 30 years after Mario Rizzetto and colleagues described a new antigen in livers of HBsAg-positive patients called the "delta antigen", a re-emerging interest in hepatitis delta is currently observed. The state-of-the art on basic and clinical research on hepatitis delta was presented during a monothematic conference organized by the European Association for the Study of the Liver (EASL) in September 2010. Hepatitis delta is caused by infection with the hepatitis D virus (HDV) which requires presence of HBsAg for complete replication and transmission. Recent data confirmed the severe long-term course of HDV infection with high rates of hepatic decompensation while controversial data on the risk for the development of hepatocellular carcinoma were reported. Pegylated interferon alpha can lead to sustained HDV RNA elimination in about one quarter of patients while HBV polymerase inhibitors are ineffective against HDV. Novel treatment options include prenylation inhibitors and HBV entry inhibitors which are currently in early clinical development. © 2011 John Wiley & Sons A/S.


Cornberg M.,Hepatology and Endocrinology | Jaroszewicz J.,Hepatology and Endocrinology | Manns M.P.,Hepatology and Endocrinology | Wedemeyer H.,Hepatology and Endocrinology
Minerva Gastroenterologica e Dietologica | Year: 2010

Approximately 350-420 million people worldwide are chronically infected with hepatitis B virus (HBV). Chronic hepatitis B can result in liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Reactivation of hepatitis B is possible in patients with inactive or resolved hepatitis B often leading to liver failure. Those sequelae may be prevented by effective antiviral therapy. Interferon alfa, pegylated interferon alfa and five direct antiviral nucleoside and nucleotide analogues are approved for the treatment of chronic hepatitis B. Still, whom to treat, which therapy regimen to use, and when to begin treatment remain the challenges in the management HBV-infected patients. This review focuses on the current treatment concepts for chronic hepatitis B.

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