Hepatitis: Erhardt A

Cornberg M, Protzer U, Dollinger MM, Petersen J, Wedemeyer H, Berg T, Jilg W, Erhardt A, Wirth S, Schirmacher P, Fleig WE, Manns MP, Anonymous00064, Anonymous00065, Anonymous00066, Anonymous00067, Anonymous00068. · Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. · J Viral Hepat. · Pubmed #18713127 No free full text.

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Cornberg M, Protzer U, Dollinger MM, Petersen J, Wedemeyer H, Berg T, Jilg W, Erhardt A, Wirth S, Schirmacher P, Fleig WE, Manns MP. · Abteilung Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover. · Z Gastroenterol. · Pubmed #18080231 No free full text.

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Cornberg M, Protzer U, Dollinger MM, Petersen J, Wedemeyer H, Berg T, Jilg W, Erhardt A, Wirth S, Schirmacher P, Fleig WE, Manns MP. · Die Institutsangaben sind am Ende des Beitrags gelistet. · Z Gastroenterol. · Pubmed #17554641 No free full text.

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Koch S, Göbels K, Oette M, Heintges T, Erhardt A, Häussinger D. · Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf. · Dtsch Med Wochenschr. · Pubmed #16915550 No free full text.

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Lörke J, Avci A, Erhardt A, Heintges T, Häussinger D. · Klinik für Gastroenterologie, Hepatologie und Infektiologie, Heinrich-Heine-Universität, Düsseldorf. · Dtsch Med Wochenschr. · Pubmed #16049884 No free full text.

Abstract: New strategies have led to better results in the treatment of HCV infection during the last few years. At present the recommended treatment for patients with chronic hepatitis C is a combination of pegylated interferon and ribavirin. The sustained virological response rate of this combination therapy is 42 - 48 % for patients with genotype 1 after a course of 48 weeks and 80 % for patients with genotype 2 or 3 after a course of 24 weeks. New nucleoside analogs may lead to a better tolerance and better outcomes. A new approach is the long term monotherapy with pegylated interferon in order to reduce the progression of fibrosis and the incidence of cirrhotic complications. At present the effectivity of protease inhibitors and of a therapeutic immunisation with the E1 envelope protein of the hepatitis C virus are being examined. Because the optimal treatment strategy for patients with an acute hepatitis C infection is still unclear, these patients should be included in clinical studies.

Häussinger D, Erhardt A, Oette M. · Klinik für Gastroenterologie und Infektiologie, Düsseldorf. · Z Gastroenterol. · Pubmed #15314724 No free full text.

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Sagir A, Avci A, Erhardt A, Lörke J, Heintges T, Häussinger D. · Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Düsseldorf, Duesseldorf. · Dtsch Med Wochenschr. · Pubmed #15160325 No free full text.

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Sagir A, Kirschberg O, Heintges T, Erhardt A, Häussinger D. · Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinik Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. · Rev Med Virol. · Pubmed #15124231 No free full text.

Abstract: The SEN virus (SEN-V) belongs to a recently discovered group of DNA viruses whose members (SEN-V-D and SEN-V-H) are associated with post-transfusion hepatitis. It is a single-stranded circular, non-enveloped DNA virus of approximately 3600 to approximately 3800 nucleotides with at least three open reading frames (ORFs). Eight different strains of SEN-V have been identified and provisionally classified as members of the Circoviridae family, a group of small, single-stranded, non-enveloped circular DNA viruses that includes the TT virus (TTV), TUS01, SANBAN, PMV and YONBAN. Prevalences in different populations show great variability with marked differences between different countries and groups. Although parenteral transmission is very likely, other routes of transmission cannot be excluded. Mother to infant transmission has been demonstrated. The effect of SEN-V on chronic liver diseases has been studied. The influence of SEN-V on the response to HCV therapy was investigated in three studies, with contradictory results. Data for other acute and chronic liver diseases are sparse. Further studies are needed to define the pathogenesis and clinical importance of SEN-V infection.

Erhardt A, Hauck K, Häussinger D. · Klinik für Gastroenterologie, Hepatologie und Infektiologie, Heinrich-Heine-Universität, Düsseldorf. · Med Klin (Munich). · Pubmed #14685669 No free full text.

Abstract: Hepatitis C virus infection is often associated with an elevation of iron parameters. Free liver iron causes liver damage and liver fibrosis preferentially through induction of reactive oxygen species. With an allele frequency of 5-10% for the C282Y mutation and 6-30% for the H63D mutation, there is a frequent coincidence of hemochromatosis (HFE) mutations and chronic hepatitis C. There is increasing evidence that HFE homozygosity and even HFE heterozygosity are associated with an increased liver iron concentration and liver fibrosis progression in chronic hepatitis C. In addition, present data suggest an impact of iron on the outcome of interferon therapy. Thus, HFE mutations and liver iron stores seem to be important comorbid factors in chronic hepatitis C. Screening for iron parameters and HFE mutations should be considered in patients with hepatitis C.

Erhardt A, Petry W, Ebel M, Jablonowski H, Heintges T, Häussinger D. · Klinik für Gastroenterologie, Hepatologie und Infektiologie der Heinrich-Heine-Universität Düsseldorf. · Z Gastroenterol. · Pubmed #10768250 No free full text.

Abstract: Hepatitis C is one of the world's leading infectious diseases. The interferon-ribavirin combination therapy is the new standard for the treatment of hepatitis C in naive and relapse patients. Virological sustained response rates can be more than doubled by the IFN-ribavirin combination therapy compared to IFN-monotherapy and treatment duration can be reduced to six months in many cases. The IFN-ribavirin combination therapy has a high relative benefit in patients with unfavorable predictive parameters like high viral load, HCV genotype-1 infection and compensated liver cirrhosis. Anemia is the most important side effect of the guanosin analogue ribavirin. There are no official therapeutic recommendations for non-responder patients at present. These patients should be treated within controlled clinical trials. Monotherapy with PEG(pegylated)-interferons and combination therapies with PEG-interferons and ribavirin are the most promising future therapeutic options.

Petry W, Erhardt A, Heintges T, Häussinger D. · Klinik für Gastroenterologie, Hepatologie und Infektiologie, Heinrich-Heine-Universität Düsseldorf. · Z Gastroenterol. · Pubmed #10689749 No free full text.

Abstract: Nucleoside analogues are promising agents for the treatment of chronic hepatitis B infection (HBV-DNA-positive by hybridization assay). The drug being studied most intensively is Lamivudine (Zeffix) which has recently been approved in Germany. When given orally once daily (100 mg) Lamivudine is well-tolerated and suppresses HBV-DNA to undetectable levels in the majority of patients. Since relapse is frequent when medication is stopped long-term treatment (at least until seroconversion of HBeAg) is warranted. Indications for lamivudine monotherapy are patients with chronic hepatitis B in which interferon (IFN) is contraindicated or patients who did not respond to a previous course of interferon. Further indications are the HBV-DNA-positive cirrhosis prior to liver transplantation (OLT) and the HBV-reinfection after OLT. The main problem of long-term monotherapy with lamivudine is viral resistance. The clinical impact of the resistant mutants is often not clear. Withdrawal or even continuation of the medication may be acceptable approaches. Other nucleoside analogues like Entecavir or Adefovir are currently being tested in clinical studies. Famciclovir was investigated preferably in patients with decompensated liver disease or HBV-reinfection after OLT. Because of conflicting results the drug should only be used under study conditions. In IFN-naive patients with chronic hepatitis B (and compensated liver disease) alpha-interferon is still the first-line therapy. With a standard course of interferon 30-40% of the patients become seronegative for HBeAg as compared with 16-17% when treated with lamivudine for twelve months. Combination of lamivudine and interferon is not more effective than IFN alone. In the future combined antiviral treatment is likely to replace monotherapy.

Erhardt A, Gerlich W, Starke C, Wend U, Donner A, Sagir A, Heintges T, Häussinger D. · Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany. · Liver Int. · Pubmed #16911462 No free full text.

Abstract: BACKGROUND/AIMS: Chronic hepatitis D is difficult to treat. The present pilot study investigated the efficacy and tolerability of pegylated (PEG)-interferon (IFN)-alpha2b in chronic hepatitis D. PATIENTS AND METHODS: Twelve patients with chronic hepatitis D were prospectively treated with 1.5 microg/kg PEG-IFN-alpha2b for 48 weeks and followed for 24 weeks. Sustained response (SR) was defined as undetectable hepatitis delta virus (HDV) RNA by reverse transcriptase-polymerase chain reaction and normalization of alanine aminotransferase (ALT) at 6 months after treatment. Investigations included HDV RNA kinetics, determination of hepatitis B virus (HBV) and HDV genotypes and histological evaluation. RESULTS: An SR was achieved in two out of 12 of patients (17%). The negative predictive value of a less than 3 log HDV RNA decrease at month 6 was 100%. The positive predictive value of a more than 3 log HDV RNA decrease at month 6 was 67%. A marked ALT reduction at the end of treatment was observed in responders and nonresponders. Ishak histological score was comparable at baseline and significantly improved in responders compared with nonresponders at the end of follow-up (13.5 vs. 8.0; P<0.02). CONCLUSION: The present study indicates that PEG-IFN-alpha2b is a promising treatment option in chronic hepatitis D. Nonresponders could be identified by a less than 3 log decrease of HDV RNA at 6 months of treatment.

Hinrichsen H, Benhamou Y, Wedemeyer H, Reiser M, Sentjens RE, Calleja JL, Forns X, Erhardt A, Crönlein J, Chaves RL, Yong CL, Nehmiz G, Steinmann GG. · Medizinische Universitätsklinik, Kiel, Germany. · Gastroenterology. · Pubmed #15521004 No free full text.

Abstract: BACKGROUND AND AIMS: Novel, potent, and well-tolerated hepatitis C virus (HCV) drugs are needed. BILN 2061 is a potent and specific inhibitor of HCV serine protease in vitro. Preclinical toxicology data and studies in healthy volunteers supported the administration of BILN 2061 to patients with HCV infection. METHODS: The antiviral efficacy, pharmacokinetics, and tolerability of 25, 200, and 500 mg BILN 2061 twice daily given as monotherapy for 2 days in 31 patients infected with chronic genotype 1 HCV infection and with minimal liver fibrosis (Ishak score of 0-2) were assessed in a placebo-controlled, double-blind pilot study. In 2 subsequent placebo-controlled studies of similar design, 200 mg BILN 2061 twice daily was administered for 2 days to 10 patients with advanced liver fibrosis (Ishak score of 3 or 4) and to 10 patients with compensated cirrhosis (Ishak score of 5 or 6). RESULTS: Viral RNA reductions of 2-3 log 10 copies/mL were achieved in most of the patients. There was a trend toward a higher number of patients receiving 500 mg BILN 2061 achieving a viral RNA reduction > or =3 log(10) copies/mL as compared with patients receiving 25 mg BILN 2061. Advanced fibrosis or compensated cirrhosis did not affect the antiviral efficacy of BILN 2061. BILN 2061 was well tolerated in all studies. CONCLUSIONS: BILN 2061 is a well-tolerated and very active compound that reduced serum viral RNA concentrations after 2 days of treatment in patients infected with genotype 1 HCV independent of the degree of fibrosis. Nevertheless, further clinical trials are on hold pending resolution of animal toxicity issues.

Erhardt A, Behlen-Wilm U, Adams O, Donner A, Heintges T, Häussinger D. · Klinik für Gastroenterologie, Hepatologie und Infektiologie, Heinrich-Heine-Universität, Düsseldorf, Germany. · Dig Dis Sci. · Pubmed #12772791 No free full text.

Abstract: Combination therapy of interferon-alpha2b and ribavirin was prospectively evaluated in 20 patients with chronic replicative hepatitis and persistently normal ALTs. Patients with normal ALTs on three or more occasions within 6 months received interferon-alpha2b 3 MU three times a week with ribavirin 1000-1200 mg everyday for 12 months and had a follow-up of 6 months. HCV genotype 1 was found in 16, and HCV genotype 2 or 3 in 4 patients. No patient experienced an ALT elevation during therapy. Ten of 20 patients (50%) cleared virus at the end of treatment. In an intent-to-treat analysis, a sustained virological response (SR) was achieved in 8 of 20 patients (40%). Nonresponse occurred in 5 patients. Relapse and breakthrough were seen in 2 patients each. Treatment was discontinued in 3 patients due to side effects. Interferon (IFN) ribavirin combination therapy is effective in patients with normal ALTs and appears superior to IFN monotherapy.

Erhardt A, Reineke U, Blondin D, Gerlich WH, Adams O, Heintges T, Niederau C, Häussinger D. · Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-University of Düsseldorf, Düsseldorf, Germany. · Hepatology. · Pubmed #10706563 No free full text.

Abstract: In chronic replicative hepatitis B the significance of mutations in the basic core promoter (BCP), core upstream regulatory sequences (CURS) and negative regulatory element (NRE) for response to interferon (IFN) is unknown. A sequence analysis of the NRE, CURS, BCP, and precore region was performed from sera of 96 patients with chronic replicative hepatitis B (64 hepatitis B e antigen [HBeAg]-positive patients and 32 HBeAg-negative patients) treated with alfa-IFN (IFN-alpha). The overall sustained response (SR) rate to IFN was 30% with no significant difference between HBeAg-positive and HBeAg-negative patients. IFN responsiveness correlated to hepatitis B virus (HBV)-DNA levels, hepatitis B surface antigen (HBsAg) levels, the number of mutations in the complete BCP, especially nucleotide (nt) region 1753 to 1766 and mutations at nt 1762 and 1764. In HBeAg-positive hepatitis, SR to IFN was associated with a high number of mutations in the BCP (P <.04) and nucleotide region 1753 to 1766 (P <.015) as well as mutations at nucleotide 1764 (P <.007). In HBeAg-negative hepatitis, SR to IFN correlated with a low number of mutations in the BCP (P <.04) and nucleotide region 1753 to 1766 (P <.02) and a wild-type sequence at nt 1764 (P <.003). Prediction of IFN response was possible on the basis of nt 1764 in 77% of HBeAg-positive patients and 78% of HBeAg-negative patients. IFN response did not correlate with the occurrence of the 1896 mutation, mutations in the CURS or NRE, disease duration, ethnic origin of the patient, alanine transaminase (ALT) levels and HBV genotype. Our data suggest that HBV genome mutations located within the BCP are determinants of a response to IFN therapy.

Brenndörfer ED, Karthe J, Frelin L, Cebula P, Erhardt A, Schulte am Esch J, Hengel H, Bartenschlager R, Sällberg M, Häussinger D, Bode JG. · Department of Gastroenterology, Hepatology and Infectiology, University Hospital, Heinrich-Heine-University of Düsseldorf, Germany. · Hepatology. · Pubmed #19475692 No free full text.

Abstract: The hepatitis C virus (HCV) is a worldwide major cause of chronic liver disease with a high tendency to establish a persistent infection. To permit persistent replication of viral genomes through the cellular translation machinery without affecting host cell viability, viruses must have developed mechanisms to control cellular cascades required for sufficient viral replication, on the one hand, and to adapt viral replication to the cellular requirements on the other hand. The present study aimed to further elucidate mechanisms by which HCV targets growth factor signaling of the host cell and their implications for viral replication. The study describes a novel mechanism by which HCV influences the activation of the epithelial growth factor receptor/Akt pathway through a nonstructural (NS)3/4A-dependent down-regulation of the ubiquitously expressed tyrosine phosphatase T cell protein tyrosine phosphatase (TC-PTP). NS3/4A is demonstrated to cleave TC-PTP protease-dependently in vitro at two cleavage sites. The in vivo relevance of this finding is supported by the fact that down-regulation of TC-PTP protein expression could also be demonstrated in HCV-infected individuals and in transgenic mice with intrahepatic expression of NS3/4A. CONCLUSION: This down-regulation of TC-PTP results in an enhancement of epithelial growth factor (EGF)-induced signal transduction and increases basal activity of Akt, which is demonstrated to be essential for the maintenance of sufficient viral replication. Hence, therapeutic targeting of NS3/4A may not only disturb viral replication by blocking the processing of the viral polyprotein but also exerts unforeseen indirect antiviral effects, further diminishing viral replication.

Erhardt A, Deterding K, Benhamou Y, Reiser M, Forns X, Pol S, Calleja JL, Ross S, Spangenberg HC, Garcia-Samaniego J, Fuchs M, Enríquez J, Wiegand J, Stern J, Wu K, Kukolj G, Marquis M, Beaulieu P, Nehmiz G, Steffgen J, Anonymous00033. · Klinik für Gastroenterologie, Hepatologie and Infektiologie, Universitätsklinik Düsseldorf, Düsseldorf, Germany. · Antivir Ther. · Pubmed #19320234 No free full text.

Abstract: BACKGROUND: BILB 1941 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) RNA polymerase in vitro. METHODS: In a double-blind sequential group comparison, 96 male HCV genotype 1 patients with minimal to mild liver fibrosis (Ishak or Metavir score 0-2) were randomized (8 to active treatment and 2 to placebo per dose group) and treated with 10-450 mg BILB 1941 every 8 h over 5 days. Viral load (VL) was measured using Roche Cobas TaqMan assays. RESULTS: VL decreased by > or =1 log10 IU/ml in 2/8, 2/8, 1/8, 2/7, 0/8, 2/8 and 4/5 patients on 60, 80, 100, 150, 200, 300 and 450 mg, respectively. No response was seen with placebo. HCV subtype 1b showed better response than 1a, the effect of other covariables including prior interferon treatment was not significant. NS5B population sequencing and phenotyping identified baseline samples with reduced BILB 1941 susceptibility, but did not detect an on-treatment emergence of resistant mutants. Plasma drug levels were linear until 300 mg. No serious adverse events (AEs) were reported. AEs were mainly gastrointestinal-related (most frequent diarrhoea) and frequency increased with dose. On 450 mg, all five active-treated patients discontinued (four for gastrointestinal intolerance and one for increased aspartate aminotransferase and alanine aminotransferase levels) and the trial was discontinued. CONCLUSIONS: BILB 1941 monotherapy demonstrated antiviral activity against HCV genotype 1, but gastrointestinal intolerance precluded testing of higher doses.

Haimerl F, Erhardt A, Sass G, Tiegs G. · Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen D-91054, Germany. · J Biol Chem. · Pubmed #19001362 No free full text.

Abstract: Tumor necrosis factor-alpha (TNFalpha) stimulation of hepatocytes induces either cell survival or apoptosis, which seems to be regulated by the ubiquitin-proteasome system. Here we investigated the role of TNFalpha-induced down-modulation of the de-ubiquitinating enzyme USP2 for hepatocyte survival. Inhibition of hepatocyte apoptosis by pre-treatment with TNFalpha (TNFalpha tolerance) was analyzed in the mouse model of galactosamine/TNFalpha-induced liver injury and in actinomycin D/TNFalpha-treated primary mouse hepatocytes. The role of USP2 for TNFalpha-induced hepatocyte survival was studied using small interference RNA or an expression clone. Injection of mice or preincubation of hepatocytes with TNFalpha caused a rapid down-regulation of hepatic USP2-41kD, the predominant USP2 isoform in the liver. In vitro an artificial knockdown of USP2 inhibited actinomycin D/TNFalpha-induced hepatocyte apoptosis, which was associated with elevated levels of the anti-apoptotic protein c-Flip(L/S) and a concomitant decrease of cellular levels of the ubiquitinligase Itch, a negative regulator of c-Flip. USP2-41kD overexpression abrogated TNFalpha tolerance in vitro, prevented accumulation of c-Flip(L/S) and resulted in elevated levels of Itch. Accordingly, c-Flip(L/S) protein levels were elevated in livers of TNFalpha-tolerant mice, which correlated to a switch from JNK and ERK to p38 signaling after galactosamine/TNF re-challenge. Our results indicate that TNFalpha-induced USP2 down-regulation is an effective cytoprotective mechanism in hepatocytes. Hence, USP2 could be a novel pharmacological target, and specific USP2 inhibitors might be potential candidates for the treatment of inflammation-related apoptotic liver damage.

Sagir A, Erhardt A, Schmitt M, Häussinger D. · Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinik Düsseldorf, Düsseldorf, Germany. · Hepatology. · Pubmed #18098325 No free full text.

Abstract: Transient elastography [FibroScan (FS)] is a rapid, noninvasive, and reproducible method for measuring liver stiffness, which correlates with the degree of liver fibrosis in patients with chronic hepatitis. Whether FS is useful in the detection of preexisting liver fibrosis/cirrhosis in patients presenting with acute liver damage is unclear. Patients with acute liver damage of different etiologies were analyzed. Liver stiffness was measured during the acute phase of the liver damage and followed up to the end of the acute phase. A total of 20 patients were included in the study. In 15 of the 20 patients, initial liver stiffness values measured by FS during the acute phase of the liver damage were suggestive of liver cirrhosis. However, none of these 15 patients showed any signs of liver cirrhosis in the physical examination, ultrasound examination, or liver histology [performed in 11 of 15 (73%) patients]. A significant difference was observed in the initial bilirubin levels (5.8 +/- 6.5 mg/dL versus 15.7 +/- 11.8 mg/dL; P = 0.042) and age (32.4 +/- 17.5 years versus 49.7 +/- 15.8 years; P = 0.042) between patients with liver stiffness below or above 12.5 kPa. Six patients with initially high liver stiffness were followed up to abatement of the acute hepatitic phase; in all of them, liver stiffness values decreased to values below the cutoff value for liver cirrhosis. CONCLUSION: Transient elastography frequently yields pathologically high values in patients with acute liver damage and is unsuitable for detecting cirrhosis/fibrosis in these patients.

Sagir A, Heintges T, Akyazi Z, Oette M, Erhardt A, Häussinger D. · Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinik Düsseldorf, Moorenstr, Düsseldorf, Germany. · J Viral Hepat. · Pubmed #17697015 No free full text.

Abstract: Previous large multicentre trials reported sustained virological response (SVR) rates of 45-80% in chronically infected hepatitis C virus (HCV) patients. However, it is unclear whether such a treatment success is also achieved in daily routine and to what extent it depends on expert hepatological supervision. This was retrospectively analysed in patients presenting at our outpatient department during May 1997 and March 2004 and receiving at least one treatment dose. A total of 302 treatment-naive HCV patients [72% genotypes 1 or 4 (n = 215), 25% genotypes 2/3 (n = 78) and 3% undetermined genotype (n = 9)] were included in the analysis. Out of these, 196 patients consulted an expert hepatologist at least once every 3 months during treatment [regular visitors (RV)], whereas in 106 patients treatment was performed and supervised by a general practitioner (irregular visitors). Both patient groups did not differ in their baseline characteristics. However, the virological response rates at the end of treatment (ETR; 146/196, 74%vs 51/106, 48%, P < 0.001) and 6 months thereafter (SVR; 129/196, 66%vs 36/106, 34%, P < 0.001) were significantly higher in RV. In patients treated with pegylated-interferon (PEG-IFN)/ribavirin, this difference was statistically highly significant (P < 0.001) for HCV genotypes 1 and 4 (treated patients: SVR: 62/101, 61%vs 14/51, 27%, P < 0.001), but not for genotypes 2/3. SVR rates were also significantly better in RV with advanced liver damage [SVR 69% (22/32) vs 25% (5/20), P = 0.004]. In regular and irregular visitors treatment was discontinued in 7% (14/196) and 15% (16/106) respectively (P = 0.015). Patients with unfavourable genotypes 1 and 4 or with advanced liver damage benefit from HCV therapy supervision by a specialist, probably because of less frequent treatment interruptions or dose reductions.

Sagir A, Heintges T, Akyazi Z, Oette M, Erhardt A, Häussinger D. · Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinik Düsseldorf, Düsseldorf, Germany. · Liver Int. · Pubmed #17696934 No free full text.

Abstract: BACKGROUND: Treatment options for hepatitis C have developed rapidly in the past decade. The current treatment of choice is a combination of pegylated-interferon-alpha (PEG-IFN-alpha) and ribavirin. With the development of more therapy options, patients who failed in prior therapy hope to clear hepatitis C virus by undergoing a more effective retreatment regime. In this report, we investigated response rates to combination therapy [standard IFN-alpha or PEG-IFN-alpha and ribavirin] in patients who relapsed or failed in prior therapy. METHODS: Ninety-three patients were included in this retrospective study. All patients failed to previous IFN-alpha monotherapy (n=55) or to a combination of standard IFN-alpha and ribavirin (n=38). Fifty-nine patients were nonresponders and 34 were relapsers. Thirty-five patients were retreated with standard IFN-alpha plus ribavirin and 58 received PEG-IFN-alpha combination therapy. RESULTS: Sustained virologic response (SVR) was induced in 31% of all patients. The highest SVR rate (58%) was observed in relapsers to standard IFN-alpha combination therapy who were retreated with PEG-IFN-alpha combination therapy. The SVR rate in relapsers to standard IFN-alpha monotherapy who received a standard IFN-alpha combination therapy was 50%. Relapsers responded in a significantly higher proportion to retreatment than nonresponders (56% vs. 17%, P<0.001). Relapse to previous therapy was identified as an independent predictor for therapy response. The lowest SVR rate was observed in nonresponders to standard IFN-alpha combination therapy who were retreated with PEG-IFN-alpha combination therapy (1/26; 4%). CONCLUSIONS: In relapsers, retreatment with the most effective therapy regime to date a combination of PEG-IFN-alpha and ribavirin, is promising. However, retreatment with PEG-IFN-alpha combination therapy in nonresponders to standard IFN combination therapy is not effective.

Erhardt A, Biburger M, Papadopoulos T, Tiegs G. · Institute of Experimental and Clinical Pharmacology and Toxicology, University ofErlangen-Nuremberg, Fahrstrasse 17, D-91054 Erlangen, Germany. · Hepatology. · Pubmed #17256743 No free full text.

Abstract: The liver appears to play an important role in immunological tolerance, for example, during allo-transplantation. We investigated tolerance mechanisms in the model of concanavalin A (ConA)-induced immune-mediated liver injury in mice. We found that a single injection of a sublethal ConA dose to C57BL/6 mice induced tolerance toward ConA-induced liver damage within 8 days. This tolerogenic state was characterized by suppression of the typical Th1 response in this model and increased IL-10 production. Tolerance induction was fully reversible in IL-10 -/- mice and after blockade of IL-10 responses by anti-IL10R antibody. Co-cultures of CD4+CD25+ regulatory T cells (T(reg)s) and CD4+CD25- responder cells revealed T(reg) from ConA-tolerant mice being more effective in suppressing polyclonal T cell responses than T(reg) from control mice. Moreover, T(reg) from tolerant but not from control mice were able to augment in vitro IL-10 expression. Depletion by anti-CD25 monoclonal antibody (MAb) indicated a functional role of T(reg)s in ConA tolerance in vivo. Cell depletion studies revealed T(reg)S and Kupffer cells (KC) to be crucial for IL-10 expression in ConA tolerance. Studies with CD1d -/- mice lacking natural killer T (NKT) cells disclosed these cells as irrelevant for the tolerogenic effect. Finally, cellular immune therapy with CD4+CD25+ cells prevented ConA-induced liver injury, with higher protection by Treg from ConA-tolerized mice. Conclusion: The immunosuppressive cytokine IL-10 is crucial for tolerance induction in ConA hepatitis and is mainly expressed by CD4+CD25+ T(reg) and KC. Moreover, T(reg)s exhibit therapeutic potential against immune-mediated liver injury.

Nitschman S, Erhardt A, Häussinger A. · No affiliation provided · Internist (Berl). · Pubmed #17226008 No free full text.

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Göbel T, Vorderwülbecke S, Hauck K, Fey H, Häussinger D, Erhardt A. · Klinik für Gastroenterologie, Hepatologie und Infektiologie, Heinrich-Heine-Universität Düsseldorf, Moorenstr. 5, D-40225 Düsseldorf, Germany. · World J Gastroenterol. · Pubmed #17171788 links to  free full text

Abstract: AIM: To identify a multi serum protein pattern as well as single protein markers using surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF-MS) for detection and differentiation of liver fibrosis (F1-F2), liver cirrhosis (F4) and hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV). METHODS: Serum samples of 39 patients with F1/F2 fibrosis, 44 patients with F4 fibrosis, 34 patients with HCC were applied to CM10 arrays and analyzed using the SELDI-TOF ProteinChip System (PBS-IIc; Ciphergen Biosystems) after anion-exchange fractionation. All patients had chronic hepatitis C and histologically confirmed fibrosis stage/HCC. Data were analyzed for protein patterns by multivariate statistical techniques and artificial neural networks. RESULTS: A 4 peptide/protein multimarker panel (7486, 12,843, 44,293 and 53,598 Da) correctly identified HCCs with a sensitivity of 100% and specificity of 85% in a two way-comparison of HCV-cirrhosis versus HCV-HCC training samples (AUROC 0.943). Sensitivity and specificity for identification of HCC were 68% and 80% for random test samples. Cirrhotic patients could be discriminated against patients with F1 or F2 fibrosis using a 5 peptide/protein multimarker pattern (2873, 6646, 7775, 10,525 and 67,867 Da) with a specificity of 100% and a sensitivity of 85% in training samples (AUROC 0.976) and a sensitivity and specificity of 80% and 67% for random test samples. Combination of the biomarker classifiers with APRI score and alfa-fetopotein (AFP) improved the diagnostic performance. The 6646 Da marker protein for liver fibrosis was identified as apolipoprotein C-I. CONCLUSION: SELDI-TOF-MS technology combined with protein pattern analysis seems a valuable approach for the identification of liver cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis C. Most probably a combination of different serum markers will help to identify liver cirrhosis and early-stage hepatocellular carcinomas in the future.

Erhardt A, Lörke J, Vogt C, Poremba C, Willers R, Sagir A, Häussinger D. · Klinik für Gastroenterologie, Hepatologie und Infektiologie, Heinrich-Heine-Universität, Düsseldorf. · Dtsch Med Wochenschr. · Pubmed #17136655 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: Detection of liver cirrhosis has numerous implications because of the potential sequelae of cirrhosis. Transient elastography (Fibroscan), was evaluated as a novel, non-invasive means of assessing cirrhosis by measuring liver stiffness. METHODS: 147 consecutive patients with different forms of liver disease and histologically determined stages of liver fibrosis were prospectively studied by transient elastography. 48 patients had liver cirrhosis. RESULTS: The number of transient elastographic measurements per patient was 12+/-4 (range 6 - 30). Valid elastography measurements were available for 135 out of 147 patients (92 %). The results of transient elastography correlated positively with the histological score of liver fibrosis (r = 0.8; 95 % CI: 0.72 - 0.85; p < 0.001). Areas under the receiver operating characteristic curve (AUROC) were 0.91 for > or = F3 fibrosis (95 % CI: 0.85 - 0.96) and 0.94 for cirrhosis (95 % CI: 0.90 - 0.98). Using a cut-off value of 13 kPa for detection of liver cirrhosis a sensitivity of 90 %, a specificity of 82 %, a positive predictive value of 71 % and a negative predictive value of 95 % were obtained. CONCLUSIONS: Measuring liver stiffness by transient elastography proved to be an easy method to assess liver cirrhosis. In combination with clinical signs, ultrasound and biochemical markers noninvasive diagnosis of liver cirrhosis will be further improved.