Hepatitis: Germany

Geissler EK, Schlitt HJ. · Department of Surgery, Regensburg University Medical Center, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. · Gut. · Pubmed #19052024 No free full text.

Abstract: In the last few decades liver transplantation (LTx) has become a reliable life-saving procedure for patients with chronic end-stage liver diseases. LTx has an outstanding success rate in the first few years after allografting, especially considering that many patients are on the brink of survival at the time of transplantation. The success of LTx is owed to the pioneers who developed the surgical procedures and to researchers who discovered the medications to help prevent immunological rejection of allografts. However, several problems continue to impose serious limits on LTx today, including a shortage of donor livers, recurrence of disease (eg, hepatitis, hepatocellular cancer), preservation of long-term allograft function and the side effects of anti-rejection drugs. While the dilemma of organ shortage is not a focus of this review, we will address the latter issues as they relate to the "oldest" and "newest" approaches to immunosuppression, and discuss the prospect that recipients could potentially be made immunologically tolerant to liver transplants. Due to the critical shortage of organs, new strategies to preserve transplanted liver allografts for the longest possible time are of paramount importance.

von Laer D, Baum C, Protzer U. · Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt am Main, Germany. · Handb Exp Pharmacol. · Pubmed #19048204 No free full text.

Abstract: This chapter describes the major gene therapeutic approaches for viral infections. The vast majority of published approaches target severe chronic viral infections such as hepatitis B or C and HIV infection. Two basic gene therapy strategies are introduced here. The first involves the expression of a protein or an RNA that inhibits viral replication by targeting crucial steps of the viral life cycle or by interfering with a cellular factor required for virus replication. The major limitation of this approach is that primary levels of gene modification have generally not been sufficient to reduce the availability of target cells permissive for virus replication to a level that significantly decreases overall viral load. Thus, investigators have banked on the expectation that gene-protected cells have a sufficient selective advantage to accumulate and gain prevalence over time, a prediction that so far could not be confirmed in clinical trials. In vivo levels of gene modification can be improved, however, by introducing an additional selectable marker. In addition, a secreted antiviral gene product that exerts a bystander effect could significantly reduce overall virus replication despite relatively low levels of gene modification. In addition to these direct antiviral approaches, several strategies have been developed that employ or aim to enhance host immune responses. The innate immune response has been enhanced, for example, by the in vivo expression of interferons. Alternatively, T cells can be grafted with recombinant receptors to boost adaptive virus-specific immunity. These approaches are especially promising for chronic virus infection, where natural immune responses are evidently not sufficient to effectively control virus replication.

Müller B, Kräusslich HG. · Department of Virology, University of Heidelberg, Im Neuenheimer Feld 324, Heidelberg, D-69120, Germany. · Handb Exp Pharmacol. · Pubmed #19048195 No free full text.

Abstract: Viruses are obligatory intracellular parasites, whose replication depends on pathways and functions of the host cell. Consequently, it is difficult to define virus-specific functions as suitable targets for anti-infective therapy. However, significant progress has been made in the past 50 years towards the development of effective and specific antivirals. In particular, human immunodeficiency virus, hepatitis C virus, and hepatitis B virus, which cause chronic infections affecting millions of individuals world-wide, are a major focus of antiviral research. Initially, antivirals were mainly directed against virus-specific enzymes; more recently, drugs inhibiting the steps of virus entry or release have been developed. Rational approaches towards drug development, based on information about structure and function of viral proteins and molecular mechanisms of virus-host interactions, have become increasingly successful. Novel strategies currently explored in basic research or preclinical studies include approaches targeting host factors important for virus replication, the exploitation of the innate immune response system as well as the use of gene silencing strategies aimed at interfering with viral gene expression. Today, a number of effective virostatics targeting various viral replication steps are approved for treatment of important viral diseases. However, the use of these drugs is limited by the rapid development of antiviral resistance, which represents a central problem of current antiviral therapy.

Teschke R, Schwarzenboeck A, Hennermann KH. · Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Johann Wolfgang Goethe-University of Frankfurt/Main, Hanau, Germany. · Br J Clin Pharmacol. · Pubmed #19032721 No free full text.

Abstract: Structured causality assessment of hepatotoxicity by drugs and dietary supplements (DDS) is a major clinical challenge, since temporal associations as the sole criteria for a valid evaluation are not acceptable. Initially, a clear intuition for an ad hoc evaluation is necessary, but only provisional, and must be followed by a diagnostic algorithm using a pretest, main test and post test. The evaluation is based on a variety of items such as latency period, course of alanine aminotransferase and alkaline phosphatase after DDS discontinuation, risk factors, co-medication, previous information on hepatotoxicity of the DDS, response to rechallenge, and exclusion of other diseases. It is essential that practising and hospital physicians as well as other key health professionals, such as pharmacists, gather all information required for a sound causality assessment, obviating major discussions by expert panels, manufacturers and health agencies in face of scanty and fragmentary data. Because pharmacogenetic alterations may trigger metabolic hepatotoxicity by a few DDS, levels in plasma and urine should be measured and may be helpful for diagnosis. Concomitant genotyping of cytochrome P450 and other enzymes may also be useful in future to minimize the risk of unwanted side-effects, including toxic liver disease elicited by DDS.

Neumann-Haefelin C, Blum HE, Thimme R. · Abteilung Innere Medizin II, Universitätsklinikum Freiburg. · Dtsch Med Wochenschr. · Pubmed #18988133 No free full text.

Abstract: RNA interference is the inhibition of gene expression at the level of messenger RNA (mRNA) mediated by small RNA molecules. Small interfering RNA (siRNA) is an important immune defence mechanism in plants and non-vertebrates. In addition, synthetic siRNAs can be used to inhibit gene expression also in human cells. More than 500 microRNAs (miRNAs), however, are involved in the natural regulation of gene expression in humans, e. g., in development-specific gene expression in embryogenesis or organ development. Although a role of miRNAs in antiviral immune defence has been discussed for some time, only recently virus-promoting as well as antiviral properties of defined miRNAs have been identified in hepatitis C virus (HCV) infection. The understanding of the mechanisms of action of miRNA might lead to new antiviral and preventive strategies.

Schulte B, Stöver H, Leicht A, Schnackenberg K, Reimer J. · Universität Hamburg, BRD. · Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. · Pubmed #18985415 No free full text.

Abstract: The high prevalence and incidence rates of the hepatitis C virus (HCV) infections in drug users demonstrate the urgent necessity for a coordinated national prevention strategy. In the shadow of HIV/AIDS the necessary attention to the rapid spreading of the hepatitis C in drug users was started late, without being able to reach the public attention level of HIV/AIDS. The present efforts in the primary and secondary prevention of the hepatitis C in drug users are obviously not sufficient to reduce the prevalence with long-lasting results. Substitution treatment is of central relevance in the prevention of hepatitis C in opiate-dependent subjects, but requires, as current data of the HCV incidence of substituted opiate dependents illustrate, a stronger HCV-specific accentuation. Further settings, which are relevant for the group of intravenous drug users, have to be accessed and sensitized. Furthermore structural and political efforts are necessary, in order to develop a systematic and evidence-based answer to the challenge of the HCV spreading in drug users, in particular due to the fact that a German HCV strategy is still lacking.

Weber S, Gressner OA, Hall R, Grünhage F, Lammert F. · Department of Medicine II, Saarland University Hospital, Saarland University, Homburg/Saar, Germany. · Clin Liver Dis. · Pubmed #18984464 No free full text.

Abstract: Hepatic fibrosis, or scarring of the liver, is a nonspecific reaction to chronic liver injury. Hepatic fibrosis is commonly caused by exogenous factors such as viral hepatitis or alcohol abuse, but recent studies also indicate a genetic predisposition. Although some patients who have chronic liver diseases show only minor morphologic and functional alterations of the liver and are characterized by slow progression of disease with mild clinical symptoms, others develop pronounced hepatic fibrosis rapidly, culminating in cirrhosis, liver failure, or hepatocellular carcinoma, respectively. These well known differences in progression of hepatic fibrosis persist when controlling for age (at infection), gender, and exogenous factors in multivariate analysis, indicating that genetic factors might play important roles in the modulation of hepatic fibrosis and contribute to the variability in fibrosis progression. This review summarizes genetic determinants in hepatic fibrosis.

Thimme R, Neumann-Haefelin C, Boettler T, Blum HE. · Department of Medicine II, University Hospital Freiburg, D-79106 Freiburg, Germany. · Biol Chem. · Pubmed #18953713 No free full text.

Abstract: Hepatitis C virus (HCV) causes chronic infection in approximately two-thirds of cases, leading to chronic hepatitis, liver cirrhosis, liver disease, liver failure, and hepatocellular carcinoma in a substantial proportion of the 170 million HCV-infected individuals worldwide. It is generally accepted that the cellular immune response plays the most important role in determining the outcome of HCV infection. First, vigorous, multispecific and sustained CD4+ and CD8+ T-cell responses are associated with viral clearance. Second, depletion studies in chimpanzees, the only other host of HCV besides humans, have shown that both CD4+ and CD8+ T-cells are required for virus elimination. Third, the host's human leukocyte antigen alleles, which restrict the repertoire of CD4+ and CD8+ T-cell responses, influence the outcome of infection. Of note, protective immunity has been demonstrated in population-based studies, as well as in experimentally infected chimpanzees. Thus, a detailed understanding of the mechanisms contributing to the failure of the antiviral immune response should allow successful development of prophylactic and therapeutic vaccination strategies.

Panther E, Blum HE. · Abteilung Innere Medizin II, Universitätsklinik Freiburg. · Dtsch Med Wochenschr. · Pubmed #18946855 No free full text.

Abstract: Abnormal liver function tests occur in 3 - 5% of pregnancies for different reasons. Apart from pre-existing liver diseases liver diseases occurring during pregnancy, such as gall stones or viral hepatitis, most liver dysfunctions in pregnancy are caused by one of the five pregnancy-related liver diseases. The five known pregnancy-related liver diseases can be classified in two main categories depending on their association with or without preeclampsia. The preeclampsia-associated liver diseases are the preeclampsia itself, the HELLP-syndrome ("Hemolysis" (H), "Elevated Liver Tests" (EL), "Low Platelet Count" (LP)) and the acute fatty liver of pregnancy. Hyperemesis gravidarum and intrahepatic cholestasis of pregnancy are not associated with preeclampsia. Hyperemesis gravidarum is characterised by intractable vomiting in the first trimester of pregnancy. 50% of patients with this condition have liver dysfunction. Intrahepatic cholestasis of pregnancy presents with pruritus and elevated bile acids in the second half of pregnancy. Patients have often mild jaundice and highly elevated liver enzymes. Treatment of choice is ursodeoxycholic acid to relieve the mother's symptoms. With this condition mainly the fetus is at risk. Severe preeclampsia is the most common cause of liver dysfunction in pregnancy, and is in some cases further complicated by HELLP syndrome. The prompt delivery of the baby is the only definitive therapy. However, many life-threatening maternal complications like liver hematoma or rupture and abruptio placentae can occur. Acute fatty liver of pregnancy is also a severe illness occuring mostly in the third trimester; microvesicular fat deposition in the liver can cause liver failure with coagulopathy and encephalopathy. Only the immediate delivery of the fetus can save mother and child.

Domm S, Cinatl J, Mrowietz U. · Psoriasis-Center at the Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, Schittenhelmstr. 7, 24105 Kiel, Germany. · Br J Dermatol. · Pubmed #18945310 No free full text.

Abstract: Biologics that antagonize the biological activity of tumour necrosis factor (TNF)-alpha, namely infliximab, etanercept and adalimumab, are increasingly used for treatment of immune-mediated inflammatory diseases, including psoriasis, worldwide. TNF-alpha antagonists are known to increase the risk of reactivation and infection, particularly of infections with intracellular bacteria such as Mycobacterium tuberculosis. More frequently these agents are given to patients with viral infections. Viral hepatitis and human immunodeficiency virus infections are often present in these patients, with a considerable geographical variation. Other concomitant viral infections such as herpes, cytomegalovirus and varicella zoster virus may occur much more frequently than tuberculosis or leprosy. General recommendations about the management related to possible problems associated with anti-TNF-alpha treatment and these viral infections are lacking. This short review will give an overview of the most recent data available on the effects of anti-TNF-alpha therapy on viral infections with a particular focus on patient management and screening recommendations.

Anderson N, Borlak J. · Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai-Fuchs-Str. 1, 30625 Hannover, Germany. · Pharmacol Rev. · Pubmed #18922966 No free full text.

Abstract: Steatosis of the liver may arise from a variety of conditions, but the molecular basis for lipid droplet formation is poorly understood. Although a certain amount of lipid storage may even be hepatoprotective, prolonged lipid storage can result in an activation of inflammatory reactions and loss of metabolic competency. Apart from drug-induced steatosis, certain metabolic disorders associated with obesity, insulin resistance, and hyperlipidemia give also rise to nonalcoholic fatty liver diseases (NAFLD). It is noteworthy that advanced stages of nonalcoholic hepatic steatosis and steatohepatitis (NASH) result ultimately in fibrosis and cirrhosis. In this regard, the lipid droplets (LDs) have been discovered to be metabolically highly active structures that play major roles in lipid transport, sorting, and signaling cascades. In particular, LDs maintain a dynamic communication with the endoplasmic reticulum (ER) and the plasma membrane via sphingolipid-enriched domains of the plasma membrane-the lipid rafts. These microdomains frequently harbor receptor tyrosine kinases and other signaling molecules and connect extracellular events with intracellular signaling cascades. Here, we review recent knowledge on the molecular mechanisms of drug and metabolically induced hepatic steatosis and its progression to steatohepatitis (NASH). The contribution of cytokines and other signaling molecules, as well as activity of nuclear receptors, lipids, transcription factors, and endocrine mediators toward cellular dysfunction and progression of steatotic liver disease to NASH is specifically addressed, as is the cross-talk of different cell types in the pathogenesis of NAFLD. Furthermore, we provide an overview of recent therapeutic approaches in NASH therapy and discuss new as well as putative targets for pharmacological interventions.

Zender L, Kubicka S. · Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hanover, Hanover, Germany. · Onkologie. · Pubmed #18854656 No free full text.

Abstract: Hepatocellular carcinoma (HCC) constitutes the 5th most frequent cancer worldwide, and due to a lack of treatment options, HCC represents the 3rd most lethal cancer worldwide. The incidence of HCC is continuously rising in Europe and Northern America, which can be explained by spreading of hepatitis C virus infections. Systemic chemotherapy is not an option for most patients with HCC. The most promising strategy for systemic treatment of HCC is targeted therapy. Successful targeted therapy has to inhibit pathways which are necessary for tumor growth, even in the late stages of carcinogenesis. The p16/Rb, p53, and IGF2R checkpoints as well as oncogenic alterations of telomerase, c-myc, Wnt/beta-catenin, PI3K/Akt, hedgehog, and c-met/HGF are most frequently involved in human hepatocarcinogenesis. However, currently, the most attractive target for molecular therapy of HCC appears to be the vascular endothelial growth factor (VEGF). Phase I/II studies showed high progression-free survival rates with antibodies or small molecules targeting the VEGF receptor pathway. Recently, a randomized placebo-controlled phase III study showed that the multikinase inhibitor sorafenib, which inhibits VEGF and Raf, significantly improves survival of patients with advanced HCC and Child A cirrhosis. As a consequence of this study, sorafenib is now the first available drug for effective systemic treatment of patients with advanced HCC.

Zeuzem S, Nelson DR, Marcellin P. · JW Goethe University Hospital, Frankfurt, Germany. · Antivir Ther. · Pubmed #18839776 No free full text.

Abstract: There is a need for improved treatment strategies and new therapeutic agents to increase cure rates in chronic hepatitis C virus (HCV) infection. Ongoing trials are aimed at optimizing sustained virological response rates with pegylated interferon (PEG-IFN) plus ribavirin. For a new agent to supplant the standard of care it must augment the strengths or compensate for the weaknesses of PEG-IFN plus ribavirin. To improve cure rates on its own, a new agent must not only suppress replication of the virus, but also clear infected hepatocytes. It is now clear that new anti-HCV agents will be used, at least initially, against a backbone of PEG-IFN plus ribavirin. A broad spectrum of agents is under investigation and it is hoped that these drugs will ultimately increase cure rates, reduce the required duration of therapy, improve tolerability and possibly simplify therapy. Reductions in serum HCV RNA ranging from 2 to 5 log10 IU/ml have been obtained in human trials with NS3/4A protease inhibitors and polymerase inhibitors. A minimum of additive reductions in serum HCV RNA levels have been observed when agents in these classes have been administered with PEG-IFN plus ribavirin in treatment-naive patients. Preliminary results in non-responders to IFN are less promising. Combinations of small molecules will be needed in order to produce sustained suppression of HCV replication in the absence of the standard of care, and such large clinical trials are several years away. The treatment paradigm for chronic hepatitis C continues to evolve and will eventually incorporate new drugs as they are approved.

Zeuzem S. · Department of Medicine, JW Goethe University Hospital, Frankfurt, Germany. · Nat Clin Pract Gastroenterol Hepatol. · Pubmed #18838975 No free full text.

Abstract: Pegylated interferon alpha (peginterferon alpha) plus ribavirin is the current mainstay of treatment for patients with chronic HCV infection. When peginterferon alpha plus ribavirin is administered for the standard duration, a sustained virological response is achieved in around 50% of patients infected with HCV genotype 1 and around 80% of patients infected with HCV genotype 2 or 3. Data now suggest that treatment duration can be shortened or lengthened depending on baseline viral load and/or early on-treatment viral kinetics, offering the prospect of individualizing therapy further to improve response or to prevent treatment from being unnecessarily extended. Further efforts to optimize therapy are likely to involve the use of new anti-HCV agents, several of which are currently in the early stages of development. These agents include HCV protease inhibitors (particularly those against NS3-4A protease), HCV polymerase inhibitors (including both nucleoside and non-nucleoside analogs) and cyclophilin inhibitors. These compounds will be used, at least initially, in combination with peginterferon alpha plus ribavirin, extending the pivotal role of interferon-based therapy in the management of chronic hepatitis C.

Dienes HP, Drebber U. · Kompetenznetzwerk HepNet, Deutsche Leberstiftung, Institut für Pathologie, Universitätsklinikum Köln. · Pathologe. · Pubmed #18820914 No free full text.

Abstract: New findings have been made in recent years on the various forms of the hepatitis virus in terms of disease course, its etiopathogenetic link with comorbidities and the definition of new forms in Central Europe. Epstein-Barr virus (EBV)- and cytomegalovirus (CMV)-induced hepatitis may occur in the so-called sero-negative group of hepatitis and direct demonstration of the viral genome in paraffin liver tissues is required to confirm the diagnosis. Since diagnosis of autoimmune hepatitis in daily practice may be difficult, a scoring system with simplified criteria has recently been developed.

Beckebaum S, Sotiropoulos GC, Gerken G, Cicinnati VR. · Department of Gastroenterology and Hepatology, University Hospital Essen, Germany. · Rev Med Virol. · Pubmed #18816503 No free full text.

Abstract: The ultimate goal of treatment is suppression of viral replication to undetectable HBV-DNA levels prior to and after liver transplantation (LT) to prevent infection of the newly transplanted liver. Most published data are available from therapy with lamivudine (LAM) in pre- and post-transplant HBV patients. Add-on therapy with adefovir dipivoxil (ADV) in pre-transplant LAM-resistant patients has been shown to represent an effective antiviral strategy leading to hepatic recompensation in many cases and, eventually, removal from the waiting list. Newer nucleos(t)ide analogues such as entecavir, tenofovir and telbivudine have shown lower resistance rates than LAM and more antiviral potency in studies in the non-transplant setting. Combined hepatitis B immune globulin (HBIG) and nucleos(t)ide analogue therapy have been widely adopted as the most effective treatment strategy against recurrent HBV disease after LT. Many programs have evaluated lower doses or a shorter duration of HBIG and intramuscular versus intravenous routes of administration. Active immunisation using recombinant HBV vaccines, including the S, pre-S1 and pre-S2 regions, and those with immunostimulatory adjuvants, seem to be more immunogenic than the currently available vaccines and have been used in studies to replace HBIG. Furthermore, it has been shown that immune memory against HBV can be adoptively transferred from organ donors to transplant recipients. Nucleos(t)ide analogue combination therapies might provide an alternative to the current treatment paradigm with costly HBIG; however, experience with this new treatment regimen is very limited and controlled clinical studies are urgently warranted to investigate its safety and efficacy and to determine which nucleos(t)ide analogue combinations will be the most promising in the long term after LT.

Girndt M. · Medical Department IV, University of the Saarland, Homburg/Saar, Germany. · Drugs Aging. · Pubmed #18808207 No free full text.

Abstract: Viral hepatitis continues to be a relevant topic for haemodialysis centres, although the number of infected dialysis patients is declining in most countries. Chronic hepatitis B and C lead to detrimental complications such as liver cirrhosis and hepatocellular carcinoma. These complications can be avoided by successful antiviral treatment. In individuals with normal renal function, drug therapy of chronic hepatitis B is evolving quickly. Today there are several options but no agreed standard therapy. In the absence of renal failure, chronic hepatitis C should be treated with a combination of pegylated interferon-alpha and ribavirin. For both infections, there is no general indication to treat all patients; several criteria can be used to predict benefits and downsides. Chronic renal failure severely alters immune function, particularly activation of T lymphocytes and cytokine production by mononuclear cells. Aging further influences the immune system with deviation of T-lymphocyte differentiation. Both effects seem to act additively, leaving the elderly haemodialysis patient with extensive immune dysfunction. While these effects do not put the patient at risk of opportunistic infection, they do have a relevant effect on the clinical course of viral hepatitis. Haemodialysis patients infected with hepatitis B manifest a subclinical, often anicteric disease, and at least 60% of the infections become chronic. These patients usually do not fulfil the criteria for successful antiviral treatment, since they have normal or slightly elevated liver enzyme levels and few histological signs of liver inflammation. In addition, the prognosis in terms of cirrhosis and hepatocellular carcinoma might be more favourable than in individuals with normal renal function. The former standard treatment of chronic hepatitis B with interferon-alpha or its derivate pegylated interferon was badly tolerated in dialysis patients and associated with low efficacy. Indeed, prior to the advent of nucleoside analogues there was a clear recommendation not to treat chronic hepatitis B infection in all except a few dialysis patients. However, the newer treatment options appear to work well. In particular, there is growing evidence for the effectiveness and tolerability of lamivudine in dialysis patients, including the elderly. Use of adefovir and entecavir has also been reported in a few cases. At present, while we still do not recommend treatment, therapy with nucleoside analogues might be an option in selected patients, for example, those planning renal transplantation. The major effort against hepatitis B should be directed at vaccination and hygienic precautions to prevent the infection.Treatment of hepatitis C in patients undergoing haemodialysis is also limited by the poor tolerability of interferons. Ribavirin is contraindicated because of severe haemolytic anaemia, although a few studies have attempted to manage this with administration of high doses of erythropoetin. Those patients who complete the full course of interferon therapy may expect sustained viral responses comparable with healthy individuals, but in most trials, 30-50% of patients were forced to interrupt treatment because of adverse effects. There is no general indication to treat chronic hepatitis C in haemodialysis patients. Arguments in favour of treatment include elevated liver enzymes, histological signs of relevant liver inflammation, younger age, a virus genotype other than 1 and planned renal transplantation.

Ramadori G, Moriconi F, Malik I, Dudas J. · Department of Internal Medicine, Section of Gastroenterology and Endocrinology, Georg-August-University Goettingen, Goettingen, Germany. · J Physiol Pharmacol. · Pubmed #18802219 links to  free full text

Abstract: The liver is the largest organ of the body. It is located between the portal and the general circulation, between the organs of the gastrointestinal tract and the heart. The main function of the liver is to take up nutrients, to store them, and to provide nutrients to the other organs. At the same time has the liver to take up potentially damaging substances like bacterial products or drugs delivered by the portal blood or microorganisms, which reach the circulation. The liver is not only an important power and sewage treatment plant of the body. In fact, the liver is probably the best example for a cheap recycling system. Both parenchymal and nonparenchymal liver cells participate in the clearance activities. The function of the liver as clearance organ, however, harbors the danger that the substances that should be degraded and/or eliminated lead to tissue damage. Thus, effective defense mechanisms are necessary. Among the nonparenchymal cells Kupffer cells, sinusoidal endothelial cells, and natural killer (NK) lymphocytes exert cellular defense functions for the whole body but also for the liver itself. Furthermore, each cell type of the liver, including the hepatocytes, possesses its own defense apparatus.

Billerbeck E, Thimme R. · Department of Medicine II, University Hospital Freiburg, Freiberg, Germany. · Hum Immunol. · Pubmed #18789990 No free full text.

Abstract: Regulatory T cells (T(reg) cells) play an important role in the regulation and suppression of immune responses to self- and foreign antigens. Suppressed and impaired host immune responses are a major characteristic of many persistent human virus infections, such as those caused by human immunodeficiency virus (HIV), hepatitis C virus (HCV), and herpes virus. It has recently become evident that immune regulation mediated by T(reg) cells may comprise one mechanism that contributes to the impairment of virus-specific immune responses. Indeed, during viral infection, the generation of distinct subsets of CD4+ as well as CD8+ T(reg) cells has been reported. The phenotypic and functional heterogeneity of T(reg) cell subsets involved in the suppression of virus-specific immune responses suggests that different mechanisms and factors contribute to the generation of those cells during viral infection. This review focuses on the CD8+ T(reg) cell subset and summarizes current knowledge about the induction and function of CD8+ T(reg) cells in persistent human virus infections.

Gröner A. · CSL Behring GmbH, Marburg, Germany. · Haemophilia. · Pubmed #18786011 No free full text.

Abstract: Plasma-derived factor VIII (FVIII) and von Willebrand Factor (VWF)/FVIII concentrates have been successfully used to treat haemophilia since the late 1960s. These products are derived from pools of plasma donations that may contain viral contaminants - including hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) - and may therefore present a transmission risk to recipients. To ensure the safety of Haemate P/Humate-P, a plasma-derived VWF/FVIII concentrate, donors of plasma are carefully selected and all donations are screened for viral antigens (HBV), virus-specific antibodies (HIV-1/2, HCV) and genomic material [hepatitis A virus, HBV, HCV, HIV-1 and high titres of human parvovirus B19 (B19V)]. As a quality control measure, plasma pools for fractionation are only released for further processing when non-reactivity has been demonstrated in serological and genome amplification assays. The manufacturing process for plasma-derived products, especially the fundamental procedure of pasteurization, is effective in inactivating and/or removing a wide variety of viruses that may potentially be present despite the screening process. This has been demonstrated in virus validation studies using a range of different viruses. New emerging infectious agents, including prions, which potentially pose a threat to recipients of plasma derivatives, are also the subject of safety evaluations. The multiple precautionary measures that are inherent in the overall production process of Haemate P/Humate-P have resulted in an excellent safety record, documented during 25 years of clinical use, and will help to maintain the high safety margin in the future.

Sunderkötter C, de Groot K. · Klinik und Poliklinik für Dermatologie, Universitätsklinikum Münster. · Hautarzt. · Pubmed #18777639 No free full text.

Abstract: Treatment and course of leukocytoclastic immune-complex vasculitis (LcV) depend on absence or presence of IgA in immune complexes [Henoch-Schoenlein-Purpura (PSH)]. LcV due to IgG- or IgM-containing immune complexes has a better prognosis. If triggers cannot be detected or avoided, symptomatic treatments are usually sufficient due to a usually favourable course. When hemorrhagic blisters suggest incipient skin necrosis corticosteroids are indicated. For chronic or relapsing LcV we suggest colchicine or dapsone. In adults with PSH and severe glomerulonephritis there is insufficient evidence for the efficacy of glucocorticoids; but e.g. ACE inhibitors can be helpful depending on symptoms. In cryoglobulinemic vasculitis underlying diseases (often plasmocytoma or hepatitis C) should be treated, sometimes supplemented by plasmapheresis. Dapsone or colchicine are usually started for urticarial vasculitis. ANCA-associated systemic vasculitis requires rapid and aggressive induction therapy, usually with glucocorticoids and cyclophosphamide. In classic polyarteriitis nodosa glucocorticoids improve prognosis, in polyarteriitis nodosa cutanea colchicine or dapsone are more appropriate. Giant cell arteriitis requires rapid therapy with glucocorticoids. For livedo vasculopathy antithrombotic measures are required with low molecular heparin or antagonists to vitamin K, for maintenance dipyridamol und aspirin.

Wiegand J, Deterding K, Cornberg M, Wedemeyer H. · Department of Internal Medicine, Medical Clinic and Polyclinic II, University of Leipzig, Leipzig, Germany. · J Antimicrob Chemother. · Pubmed #18776191 No free full text.

Abstract: Early control in the acute phase of hepatitis C infection is an attractive therapeutic goal in order to shorten disease duration and infectivity, to prevent chronicity and progression to advanced liver disease and to avoid eventual therapeutic non-response in the later stages of chronic hepatitis C. Over the past decade, different interferon-based treatment options have been developed, which lead to sustained virological response rates of up to 98%. The present article summarizes the successful invention of immediate and delayed strategies in acute hepatitis C monoinfection, critically discusses potential limitations and illustrates the therapeutic challenges of the near future.

Zeuzem S, Berg T, Moeller B, Hinrichsen H, Mauss S, Wedemeyer H, Sarrazin C, Hueppe D, Zehnter E, Manns MP. · Zentrum der Inneren Medizin, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany. · J Viral Hepat. · Pubmed #18761607 No free full text.

Abstract: The current preferred treatment for patients with hepatitis C virus (HCV) is combination therapy consisting of pegylated interferon alfa and ribavirin (RBV) for 24-48 weeks. Although this approach appears to be highly effective for patients with HCV genotypes 2 or 3, who have a sustained virological response (SVR) of approximately 80%, the treatment algorithm is less effective for patients with HCV genotype 1, as these patients have SVR rates of just 40-50%. In order to improve treatment outcomes, this article explores potential approaches for the optimization of treatment for patients with HCV genotype 1: considering shorter treatment periods for patients with a rapid virological response (RVR), increasing treatment periods for slow responders, and increasing RBV dose are all suggestions. Results from clinical trials suggest that approximately 20% of the HCV genotype 1-infected population are slow responders, and around 15% of all HCV genotype-1 infected patients could benefit from a shorter treatment duration without compromising the SVR rate. Interest has also focused on whether treatment duration could be individualized in some patients with genotype 2 and 3 infection. Here all the findings from recent studies are translated into practical advice, to help practitioners make evidence-based treatment decisions in everyday clinical practice. Although there are areas where currently available data do not provide conclusive evidence to suggest amending treatment approaches, there is clearly potential for individualized treatment in all aspects of hepatitis treatment in the future.

Lippert B. · Fakultät Chemie, Technische Universität Dortmund, Otto-Hahn-Strasse 6, D-44227 Dortmund. · Chem Biodivers. · Pubmed #18729108 No free full text.

Abstract: Functional and crystallographic analyses of catalytically active RNA molecules ('ribozymes') have revealed a multitude of different routes by which nature accomplishes cleavage reactions of the RNA sugar-phosphate backbone. While there is agreement that these reactions involve general acid-base chemistry, the choice of 'acid' and of 'base' appears to be quite versatile. Among the numerous surprises that have emerged from these studies in recent years is the phenomenon of 'shifted pK(a) values' of nucleobases, hence, the fact that pK(a) values of isolated nucleobases in H(2)O can be shifted in either direction--upward or downward--into the physiological pH range, and that consequently allows these nucleobases to function as 'acids' or 'bases'. Another change in paradigm in recent years relates to the role of divalent metal ions in these catalytic reactions, which points to the possibility of an indirect involvement in the catalytic cycle rather than necessarily to a direct participation, as in the case with the hepatitis delta virus ribozyme. In this review, basic features of nucleobases and/or aqua ligand pK(a) shifts caused by metal coordination and H-bonding are discussed.

Kau A, Vermehren J, Sarrazin C. · Zentrum der Inneren Medizin, Medizinische Klinik 1, Klinikum der JW Goethe-Universität, Frankfurt am Main, Germany. · J Hepatol. · Pubmed #18715665 No free full text.

Abstract: Treatment predictors are important tools for the management of therapy in patients with chronic hepatitis B and C virus (HBV, HCV) infection. In chronic hepatitis B, several pretreatment parameters have been identified for prediction of virologic response to interferon alfa-based antiviral therapies or treatment with polymerase inhibitors. In interferon alfa and pegylated interferon alfa-treated patients, low baseline HBV DNA concentrations, HBV genotype A (B), and high baseline ALT levels are significantly associated with treatment response. In patients treated with nucleos(t)ide analogues, low baseline HBV DNA but not viral genotype is positively associated with virologic response. During treatment the best predictor of response is HBV DNA kinetics. Early viral suppression is associated with favourable virologic response and reduced risk for subsequent resistance mutations. For the current standard treatment with pegylated interferon alfa and ribavirin in patients with chronic hepatitis C, infection with HCV genotypes 2 and 3, baseline viral load below 400,000-800,000 IU/ml, Asian and Caucasian ethnicity, younger age, low GGT levels, absence of advanced fibrosis/cirrhosis, and absence of steatosis in the liver have been identified as independent pretreatment predictors of a sustained virologic response. After initiation of treatment, initial viral decline with undetectable HCV-RNA at week 4 of therapy (RVR) is the best predictor of sustained virologic response independent of HCV genotype.