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Approximately 70,000 people are infected with hepatitis C virus in Hungary, and more than half of them are not aware of their infection. From the point of infected individuals early recognition and effective treatment of related liver injury may prevent consequent advanced liver diseases and complications (liver cirrhosis, liver failure and liver cancer) and can increase work productivity and life expectancy. Furthermore, these could from prevent further spread of the virus as well as reduce substantially long term financial burden of related morbidity, as a socioeconomic aspect. Pegylated interferon + ribavirin dual therapy, which is available in Hungary since 2003, can clear the virus in 40-45% of previously not treated (naïve), and in 5-21% of previous treatment-failure patients. Addition of a direct acting first generation protease inhibitor drug (boceprevir or telaprevir) to the dual therapy increases the chance of sustained viral response to 63-75% and 59-66%, respectively. These two protease inhibitors are available and financed for a segment of Hungarian patients since May 2013. Between 2013 and February 2015, other direct acting antivirals and interferon-free combination therapies have been registered for the treatment of chronic hepatitis C with a potential efficacy over 90% and typically with a short duration of 8-12 weeks. Indication of therapy includes exclusion of contraindications to the drugs and demonstration of viral replication with consequent liver injury, i.e., inflammation and/or fibrosis in the liver. Non-invasive methods (elastography and biochemical methods) are accepted and preferred for staging liver damage (fibrosis). For initiation of treatment accurate and timely molecular biology tests are mandatory. Eligibility for treatment is a subject of individual central medical review. Due to budget limitations therapy is covered only for a proportion of patients by the National Health Insurance Fund. Priority is given to those with urgent need based on a Hungarian Priority Index system reflecting primarily the stage of liver disease, and considering also additional factors, i.e., activity and progression of liver disease, predictive factors of treatment and other special issues. Approved treatments are restricted to the most cost-effective combinations based on the cost per sustained viral response value in different patient categories with consensus between professional organizations, National Health Insurance Fund and patient organizations. More expensive therapies might be available upon co-financing by the patient or a third party. Interferon-free treatments and shorter therapy durations preferred as much as financially feasible. A separate budget is allocated to cover interferon-free treatments for the most-in-need interferon ineligible/intolerant patients, and for those who have no more interferon-based therapy option.Magyarországon 70000 egyén lehet fertőzött hepatitis C-vírussal, nagyobbik részük nem tud a fertőzöttségéről. A fertőzés időben történő felfedezése és meggyógyítása a beteg szempontjából a munkaképesség megőrzését, az életminőség javulását, a májzsugor és a májrák megelőzését, valamint a betegségmentes várható élettartam meghosszabbodását, míg a beteg környezete és a társadalom szempontjából a továbbfertőzés veszélyének megállítását, a későbbi súlyos májbetegségekből adódó egészségügyi ráfordításigény jelentős csökkenését eredményezi. A 2003 óta alkalmazott pegilált interferon+ribavirin kettős kezeléssel a hazánkban dominálóan 1-es genotípussal fertőzött, korábban terápiában nem részesült betegek 40–45%-a, a korábban sikertelenül kezeltek 5–21%-a gyógyítható meg. 2011-ben a korábbiaknál lényegesen hatékonyabb, két új, direkt antivirális hatású proteázgátló szer került forgalomba (boceprevir és telaprevir). A készítmények – az előrehaladott stádiumban lévő májbeteg számára – 2013 májusa óta hazánkban is finanszírozottá váltak. 2013 és 2015. február között újabb direkt ható antivirális szerek kerültek törzskönyvezésre. Ezek kombinációival rövidebb időtartamú (8–24 hetes), 90% feletti gyógyulási arányt biztosító interferonmentes kezelés válik lehetővé. A kezelés indikációja – az ellenjavallatok kizárása után – a vírusnukleinsav és a májbetegség kimutatása. Utóbbit a gyulladásos aktivitás és/vagy a májfibrosis mértéke (stádium) határozza meg. A stádium meghatározására az invazív májbiopszia mellett a nem invazív elasztográfiás és validált biokémiai fibrosistesztmódszerek alkalmazhatók. A kivizsgálás és a kezelés során fontos a virológiai vizsgálatok gyors és megbízható elvégzése. Hazánkban az Egészségügyi Alapból történő kezelés engedélyezéshez kötött. A szakmailag indokolt kezelés finanszírozási korlátok miatt csak a betegek egy részénél kerül engedélyezésre. A sorrend alapja az úgynevezett Prioritási Index. Ez a májbetegség stádiuma mellett figyelembe veszi a betegség aktivitását, progresszióját, a kezelés sikerességének várható esélyét és további meghatározott speciális szempontokat is. Az egyes betegcsoportokban használható készítményeket az egy beteg meggyógyításához szükséges átlagos kezelési költség alapján a finanszírozóval egyeztetett, időszakosan aktualizált finanszírozási algoritmus határozza meg. A lehetőségek határai között előnyt élveznek a nagy hatékonyságú és biztonságos interferonmentes, illetve a rövidebb időtartamú kezelések. Az interferonalapú terápiára alkalmatlan betegek interferonmentes kezelése külön keretből, külön Prioritási Index alapján történik, a szóba jövő gyógyszerek költséghatékonyságának figyelembevételével. Orv. Hetil., 2015, 156(9), 343–351.

Diagnosis and treatment of hepatitis B and D virus infections mean that the patient is able to maintain working capacity, increase quality of life, prevent cancer, and prolong life expectancy, while the society benefits from eliminating the chances of further transmission of the viruses, and decreasing the overall costs of serious complications. The guideline delineates the treatment algorithms for 2014, which is agreed on a consensus meeting of specialists involved in the treatment of the above diseases. The prevalence of hepatitis B virus infection in the Hungarian general population is 0.5-0.7%. The indications of treatment is based upon viral examinations (including viral nucleic acid determination), determinations of disease activity and stage (including biochemical, pathologic, and/or non-invasive methods), and excluding contraindications. To avoid unnecessary side effects and for cost-effective approach the guideline emphasizes the importance of quick and detailed virologic evaluations, the applicability of transient elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection can be pegylated interferon for 48 weeks or continuous entecavir or tenofovir therapy. The latter two must be continued for at least 12 months after hepatitis B surface antigen seroconversion. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection.A hepatitis B- és D-vírus-fertőzés időben történő felfedezése és kezelése a beteg szempontjából a munkaképesség megőrzését, az életminőség javulását, rákmegelőzést, valamint a betegségmentes várható élettartam meghosszabbodását, a beteg környezete és a társadalom szempontjából a továbbfertőzés veszélyének megállítását és a kezelés révén a későbbi súlyos májbetegségekből adódó jelentős egészségügyi ráfordításigény-csökkenést jelent. Az irányelv célja a 2014. évre érvényes, a kezelőorvosok konszenzusán alapuló kezelési rend rögzítése. A magyar lakosság 0,5–0,7%-át sújtó hepatitis B-vírus-fertőzés kezelésének indikációja a vírusdiagnosztikán (benne vírusnukleinsav kimutatása), a májbetegség aktivitásának és stádiumának értékelésén (beleértve biokémiai, patológiai és/vagy nem invazív vizsgálómódszereket), valamint az ellenjavallatok kizárásán alapul. Az ajánlás hangsúlyozza a kivizsgálás során a gyors és részletes virológiai vizsgálatok jelentőségét, a biopszia mellett a tranziens elasztográfia, illetve egyéb, validált, noninvazív tesztek alkalmazhatóságát csakúgy, mint a terápia vezetésében a vírusnukleinsav-titer követésének nélkülözhetetlenségét mind a mellékhatások elkerülése, mind a költséghatékonyság szempontjából. Az idült hepatitis B kezelésében egyaránt első választás lehet a határozott – egyéves – időtartamú pegilált interferon vagy a folyamatos entecavir- vagy tenofovirkezelés, amelyet a hepatitis B felszíni antigén szerokonverziója után még legalább 12 hónapig kell folytatni. Az adefovir leginkább kombinációban javasolható. Nem megfelelő első választás a lamivudin, az ezt már szedő betegeket hatástalanság esetén másik szerre kell átállítani. Fontos az immunszuppresszív kezelésben és/vagy biológiai terápiában részesülő betegek megfelelő antivirális kezelése. Egyidejű hepatitis D esetén pegilált interferon kezelés szükséges. Orv. Hetil., 2014, 155(Szuppl. 2), 25–35.

Background. Recently we demonstrated that gastric mucosa of rats can synthesize, store and release dopamine. Out of five different subtypes, mRNA of D5 (=D1b) dopamine receptor is very abundant in the gastric epithelium. D1 receptor selective dopamine agonists have been shown to protect against experimental gastro-duodenal lesions. Aims. To test the hypothesis that protective effects of dopamine involve D5 receptors, mucosal lesions were induced in D5 receptor deficient (KO) and wild-type (WT) mice using cysteamine. Morphology and gastric acid secretion of D5 KO mice were also studied. Methods. Single doses of 600 mg/kg, 300 mg/kg cysteamine or vehicle were administered subcutaneously to fasted animals. After 24 h, number and severity of gastro-duodenal lesions were analyzed. Basal and histamine-induced maximal gastric acid output were measured by a stomach-sac wash-through method. Results. All the KOs in the 600 mg/kg cysteamine group died within 4 h showing symptoms of toxicity while three out of four WTs survived (P

The aim of this study was to investigate the Helicobacter pylori (Hp) status of patients who underwent successful eradication therapy 1 year prior to the study and to evaluate their current symptoms. Methods : all of the patients were initially evaluated by oesophago-gastro-bulboscopy and the Hp status was determined by at least two different methods [rapid urease test, histology or urea breath test (UBT)]. The Hp infection was treated with a 1-week triple therapy protocol, and the UBT was repeated 4–6 weeks later. We invited back 110 patients who had negative post-eradication UBT results 12±3 months prior to the study period. UBT was repeated and a questionnaire was completed about the previous and present complaints and medication. Results : 80 of the 110 patients (73%) came back for the follow-up. Twenty five patients had peptic ulcer disease, 36 patients had gastritis or duodenitis without erosive lesions, and 19 patients had erosive form of gastritis or duodenitis initially. All of the patients except one in the erosive gastritis group had negative control UBT 1 year after the eradication, which means 1.25% recurrence rate within 1 year. The eradication therapy completely revealed the symptoms of 16 patients in the ulcer group (64%), 13 patients in the gastroduodenitis group (36%, P =0.03 vs. ulcer patients), 10 patients with erosive gastroduodenitis (52%), but this was only temporary. One year after the eradication therapy seven of the ulcer patients (28%), 11 patients with gastroduodenitis (31%) and seven patients with erosive gastroduodenitis (37%) were symptom-free. Most of the patients had epigastric pain (44%), heartburn (43%) and/or abdominal distension (33%). Nine ulcer patients (36%), 10 patients with gastroduodenitis (28%) and five patients with erosive gastroduodenitis (26%) were taking H 2 -blockers regularly. Conclusion : the 1-month post-eradication UBT was probable true negative in all of the evaluated cases, since 79 patients (98.75%) were also negative after 1 year. The Hp recurrence rate is very low (1.25%) in a 1-year period. The symptoms were relieved shortly after eradication therapy in the majority of patients with ulcer disease or erosive lesions. However, significantly smaller portion of the patients with gastroduodenitis became symptom-free. Only about one third of the treated patients remained symptom-free 1 year after the eradication.

Cellular distribution of vesicular monoamine transporters (VMATs), known to regulate vesicular storage and release of biogenic amines (i.e., catecholamines, serotonin, histamine, etc.), have been studied in the rat stomach using in situ hybridization histochemistry (ISHH) and immunohistochemical (IHC) techniques. 35S-UTP labeled riboprobes showed that mRNAs of both VMATs are expressed in the gastric mucosa. A combination of ISHH and IHC verified that most of the parietal cells (among other epithelial cells) express mRNA of the peripheral type transporter (VMAT1) while enterochromaffin-like cells (ECL) of the fundic mucosa express mRNA of the central type (VMAT2). In addition, with double fluorescent IHC we detected VMAT1 protein in serotoninergic enterochromaffin cells (EC) of the stomach and in gastrin producing G cells of the antral mucosa. Similarly to the fundus, VMAT2 protein was present in ECL cells and in the enteric plexus. Surprisingly, serotonin- and/or histamine-containing cells in the connective tissue compartments of the stomach (i.e., lamina propria and submucosa), immunoreactive for a mast cell specific antigen, displayed neither VMATI nor VMAT2 immunoreactivity. Distribution of VMATs in the rat stomach support our previous observations on aminergic properties of two important gastrointestinal (GI) epithelial cell populations primarily known for other specific secretory products, i.e. dopaminergic properties of acid producing parietal cells and histaminergic properties of gastrin producing G cells. These data emphasize the existence of a non-neuronal, intrinsic aminergic system in the GI tract.

Background Previous studies have shown that single nucleotide polymorphisms (SNP) in IL28B and IL10R are associated with sustained virological response (SVR) in chronic hepatitis C patients treated with pegilated interferon plus ribavirin (P/R). The present study extends our earlier investigations on a large East-Central European cohort. The allele frequencies of IL28B and IL10R in genotype 1 HCV infection were compared with that of healthy controls for the purpose of examining the relationship between the polymorphisms and the SVR to P/R treatment. Methods A total of 748 chronic HCV1 infected patients (365 male, 383 female; 18–82 years) and 105 voluntary blood donors as controls were enrolled. Four hundred and twenty HCV patients were treated with P/R for 24–72 weeks, out of them 195 (46.4%) achieved SVR. The IL28 rs12979860 SNP was determined using Custom Taqman SNP Genotyping Assays. The IL10R −1087 (also known as IL10R −1082 (rs1800896) promoter region SNP was determined by RT-PCR and restriction fragment length polymorphism analysis. Results The IL28B CC genotype occurred with lower frequency in HCV patients than in controls (26.1% vs 51.4%, p

Introduction: On-treatment HCV RNA measurements are crucial for the prediction of a sustained virological response (SVR) and to determine treatment futility during protease inhibitor-based triple therapies. In patients with advanced liver disease an accurate risk/benefit calculation based on reliable HCV RNA results can reduce the number of adverse events. However, the different available HCV RNA assays vary in their diagnostic performance. Aim: To investigate the clinical relevance of concordant and discordant results of two HCV RNA assays during triple therapy with boceprevir and telaprevir in patients with advanced liver fibrosis/cirrhosis. Methods: We collected on-treatment samples of 191 patients with advanced liver fibrosis/cirrhosis treated at four European centers for testing with the Abbott RealTime (ART) and COBAS AmpliPrep/COBAS TaqMan HCV v2.0 (CTM) assays. Results: Discordant test results for HCV RNA detectability were observed in 23% at week 4, 17% at week 8/12 and 9% at week 24 on-treatment. The ART detected HCV RNA in 41% of week 4 samples tested negative by the CTM. However, the positive predictive value of an undetectable week 4 result for SVR was similar for both assays (80% and 82%). Discordance was also found for application of stopping rules. In 27% of patients who met stopping rules by CTM the ART measured levels below the respective cut-offs of 100 and 1000 IU/ml, respectively, which would have resulted in treatment continuation. In contrast, in nine patients with negative HCV RNA by CTM at week 24 treatment would have been discontinued due to detectable residual HCV RNA by the ART assay. Importantly, only 4 of these patients failed to achieve SVR. Conclusion: Application of stopping rules determined in approval studies by one assay to other HCV RNA assays in clinical practice may lead to over and undertreatment in a significant number of patients undergoing protease inhibitor-based triple therapy.

Aim: Dual peginterferon/ribavirin therapy remains a viable option for patients with chronic hepatitis C, because of the high cost of Direct-acting Antiviral Agents (DAA). We assessed real-life practice and treatment outcomes in Hungarian treatment-naive HCV genotype 1-infected patients who received peginterferon alfa-2a/ ribavirin treatment. Methods: This analysis of patients enrolled in Hungary as part of a large, multinational cohort study (PROPHESYS) included treatment-naive patients with HCV genotype 1 mono-infection who were prescribed peginterferon alfa-2a plus ribavirin. Results: Of 654 patients included in the analysis, 68% completed ≥ 80% of the planned duration of treatment (93% and 87% received ≥ 80% of the planned doses of peginterferon alfa-2a and ribavirin, respectively) and 23% stopped treatment prematurely because of the insufficient virologic response. Virologic response rates (HCV RNA < 50 IU/mL) were 20.3%, 55.2%, and 63.3% by Week 4, 12, and at the end of treatment (EOT), respectively, and a sustained virologic response 24 weeks post-treatment (SVR24) was achieved in 45.9% of patients. In patients with a virologic response at EOT, the relapse rate was 27.4%. SVR24 rates were 63% in patients who received ≥ 80% of the planned treatment and 55% in patients with lower exposure. Treatment was prolonged to ≥ 72 weeks in 51 patients with HCV RNA ≥ 50 IU/mL at Week 12, and < 50 IU/mL at Week 24, among whom the SVR24 rate was 35%. Conclusion: This analysis shows that SVR24 rates achieved in randomized trials can be reproduced in real-world settings by maintaining high rates of adherence and compliance with responseguided therapy.

Gilead Sciences The disease burden of hepatitis C virus (HCV) is expected to increase as the infected population ages. A modelling approach was used to estimate the total number of viremic infections, diagnosed, treated and new infections in 2013. in addition, the model was used to estimate the change in the total number of HCV infections, the disease progression and mortality in 2013-2030. Finally, expert panel consensus was used to capture current treatment practices in each country. Using today's treatment paradigm, the total number of HCV infections is projected to decline or remain flat in all countries studied. However, in the same time period, the number of individuals with late-stage liver disease is projected to increase. This study concluded that the current treatment rate and efficacy are not sufficient to manage the disease burden of HCV. Thus, alternative strategies are required to keep the number of HCV individuals with advanced liver disease and liver-related deaths from increasing. Ctr Dis Anal, Louisville, CO 80027 USA Natl Liver Inst, Menoufia, Egypt JW Goethe Univ Hosp, Frankfurt, Germany Univ Calgary, Liver Unit, Div Gastroenterol & Hepatol, Calgary, AB, Canada Ankara Univ, Dept Gastroenterol, Sch Med, TR-06100 Ankara, Turkey Hosp Santo Antonio Capuchos, Dept Gastroenterol, Ctr Hosp Lisboa Cent, Lisbon, Portugal Med Univ Innsbruck, A-6020 Innsbruck, Austria Univ São Paulo, Sch Med, São Paulo, Brazil Hop Henri Mondor, Serv Hepatogastroenterol, F-94010 Creteil, France Adv Tech Hlth Serv Res TAISS, Madrid, Spain Ege Univ, Izmir, Turkey Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden Karolinska Univ Hosp, Dept Gastroenterol & Hepatol Infect Dis, Stockholm, Sweden Ankara Univ, TR-06100 Ankara, Turkey Univ Leipzig, D-04109 Leipzig, Germany Osped Cantonale, Dept Gastroenterol, Bellinzona, Switzerland Univ Montreal, Dept Med, Liver Unit, Montreal, PQ H3C 3J7, Canada Fed Univ State Rio de Janeiro, Dept Gastroenterol, Rio de Janeiro, Brazil Arud Ctr Addict Med, Zurich, Switzerland Hosp Valle de Hebron, CIBERehd, Barcelona, Spain Hosp Puerta Hierro, Madrid, Spain Univ Fed Rio Grande do Sul, Hosp Clin, Porto Alegre, RS, Brazil Odense Univ Hosp, Dept Infect Dis, DK-5000 Odense, Denmark Reg Hosp Hovedstaden, Copenhagen, Denmark Univ Fed Rio de Janeiro, Dept Clin Med, Rio de Janeiro, Brazil Univ Plymouth, Peninsula Sch Med & Dent, Plymouth PL4 8AA, Devon, England Univ New S Wales, Kirby Inst, Sydney, NSW, Australia Cairo Univ, Cairo, Egypt Orebro Univ Hosp, Dept Infect Dis, Orebro, Sweden Univ Orebro, Sch Hlth & Med Sci, SE-70182 Orebro, Sweden Ain Shams Univ, Cairo, Egypt Dokuz Eylul Univ, Izmir, Turkey Karolinska Inst, Karolinska Univ Hosp, Dept Med Huddinge, Infect Dis Unit, Stockholm, Sweden Exigo Consultores, Alhos Vedros, Portugal Universidade Federal de São Paulo, Div Gastroenterol, São Paulo, Brazil Universidade Federal de São Paulo, Div Infect Dis, São Paulo, Brazil Inst Clin & Expt Med, Dept Hepatogastroenterol, Prague, Czech Republic Hosp Carlos III, CIBERehd, Madrid, Spain Univ Copenhagen, Copenhagen, Denmark Direccao Geral Saude, Lisbon, Portugal Univ Estadual Campinas, Disciplina Doencas Infecciosas, Dept Clin Med, Grp Estudo Hepatites,Fac Ciencias Med,UNICAMP, São Paulo, Brazil Wilhelminenspital Stadt Wien, Dept Internal Med 4, Vienna, Austria Univ São Paulo, Sch Med, Div Gastroenterol & Hepatol, São Paulo, Brazil Med Univ Vienna, Div Gastroenterol & Hepatol, Dept Internal Med 3, Vienna, Austria Masaryk Univ, Univ Hosp Brno, Clin Infect Dis, Brno, Czech Republic Univ Manitoba, Dept Internal Med, Sect Hepatol, Winnipeg, MB, Canada Hlth Sci Ctr, Viral Hepatitis Invest Unit, Winnipeg, MB, Canada European Liver Patients Assoc, St Truiden, Belgium Istanbul Univ, Istanbul, Turkey Univ British Columbia, British Columbia Ctr Dis Control, Vancouver, BC V5Z 1M9, Canada Aalborg Univ Hosp, Dept Med Gastroenterol, Aalborg, Denmark Aalborg Univ Hosp, Sect Mol Diagnost, Aalborg, Denmark Katholieke Univ Leuven, Univ Hosp Leuven, Louvain, Belgium Hosp Santa Maria, Dept Gastroenterol, Ctr Hosp Lisboa Norte, Lisbon, Portugal Univ Western Ontario, Div Gastroenterol, London, ON, Canada Univ Dusseldorf, Dusseldorf, Germany Univ Libre Brussels, Erasme Univ Hosp, Brussels, Belgium Univ Hosp, Div Gastroenterol & Hepatol, Geneva, Switzerland Univ Hosp, Div Clin Pathol, Geneva, Switzerland Natl Inst Publ Hlth, Natl Reference Lab Hepatitis, Prague, Czech Republic Univ Southhampton, Southampton, England Dalhousie Univ & Hepatol Serv, Capital Dist Hlth Author, Queen Elizabeth II Hlth Sci Ctr, Dept Med, Halifax, NS, Canada Dalhousie Univ & Hepatol Serv, Capital Dist Hlth Author, Queen Elizabeth II Hlth Sci Ctr, Dept Surg, Halifax, NS, Canada Univ British Columbia, Dept Gastroenterol, Vancouver, BC V5Z 1M9, Canada Assembleia Republ, Lisbon, Portugal Alfred Hosp, Melbourne, Vic, Australia Monash Univ, Melbourne, Vic 3004, Australia UCL, Div Med, UCL Inst Liver & Digest Hlth, London, England Hop Henri Mondor, Dept Sante Publ, F-94010 Creteil, France Nottingham Univ Hosp NHS Trust, Nottingham, England Biomed Res Unit, Nottingham, England Ctr Hosp Porto, Dept Infect Dis, Oporto, Portugal Cantonal Hosp St Gallen, Div Gastroenterol & Hepatol, St Gallen, Switzerland Univ Toronto, Toronto Gen Hosp, Univ Hlth Network, Toronto, ON M5G 1L7, Canada Egyptian Liver Res Inst & Hosp, Dakahliah, Egypt Monash Hlth, Melbourne, Vic, Australia Catholic Univ Louvain, Clin Univ St Luc, Brussels, Belgium Med Univ Graz, Div Gastroenterol & Hepatol, Dept Internal Med, Graz, Austria St Vincents Hosp, Dept Gastroenterol, Melbourne, Vic, Australia Univ Melbourne, Melbourne, Vic, Australia Charles Univ Prague, Dept Internal Med, Fac Med 1, Prague, Czech Republic Cent Mil Hosp, Prague, Czech Republic Univ Antwerp, B-2020 Antwerp, Belgium Deutsch Leberhilfe eV, Cologne, Germany Ghent Univ Hosp, Ghent, Belgium Univ Ghent, Belgium Hasselt Univ, Dept Hlth Econ & Patient Safety, Diepenbeek, Belgium Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany Copenhagen Univ Hosp, Hvidovre, Denmark Univ New S Wales, St George Hosp Clin Sch Med, Sydney, NSW, Australia Univ New S Wales, Sch Med Sci, Sydney, NSW, Australia Univ Zurich Hosp, Swiss HPB Hepatopancreatobiliary Ctr, CH-8091 Zurich, Switzerland Univ Zurich Hosp, Dept Gastroenterol & Hepatol, CH-8091 Zurich, Switzerland Universidade Federal de São Paulo, Div Gastroenterol, São Paulo, Brazil Universidade Federal de São Paulo, Div Infect Dis, São Paulo, Brazil Web of Science

BACKGROUND & AIMS: The gastrointestinal (GI) tract is a major source and target of somatostatin (SRIF). Recently, five pharmacologically different SRIF receptors (sst1-5) were cloned. The cellular and tissue distribution of the sst1-5 messenger RNAs (mRNAs) were studied in the rat GI tract using in situ hybridization histochemistry (ISHH). METHODS: Two sets of (35)S-uridine triphosphate (UTP)-labeled antisense and sense riboprobes were prepared for each sst. ISHH was conducted on frozen tissue samples from rat stomach, duodenum, jejunum, ileum, colon, and pancreas. RESULTS: mRNAs of all five sst-s are widely expressed in the rat GI tract. The distribution pattern for each sst mRNA was identical with both antisense probes. No specific signal was found with any of the sense probes. Each layer of the different parts of the gut expressed mRNAs of multiple sst subtypes. All organs expressed sst3 mRNA very intensely. The lowest levels of mRNA expression for all five subtypes within the GI tract were found in the pancreas. CONCLUSIONS: The widespread expression of sst mRNAs suggests a significant role for SRIF in the regulation of GI function. (Gastroenterology 1997 Jun;112(6):1948-60)

Hepatitis Registry was developed by the Hepatology Section of the Hungarian Gastroenterology Society with the contribution of the Foundation for Liver Patients. The main task was to register all interferon based treatments of chronic hepatitis C and B and to facilitate the preauthorization process. The registry helped to clarify the number and characteristics of hepatitis C patients waiting for triple therapy; 3000 previously failed patients are still eligible for protease inhibitor therapy, 40% of them already developed cirrhosis stage and 40% are null responders to the previous therapy. As a file is created for treatment authorization, the system counts automatically the Priority Index according to the calculation set in the guideline. Priority Index reflects the urgency of treatment. The most prominent parameter of the Index is the degree of fibrosis, but it also takes into account the progression rate, prognostic factors, and special situations.A Hepatitis Regiszter a Magyar Gasztroenterológai Társaság Hepatológiai Szekciója által a Májbetegekért Alapítvány közreműködésével létrehozott és üzemeltetett rendszer, amely a krónikus hepatitis B és C interferonalapú kezelésének nyilvántartására, valamint az engedélyezési folyamat elektronikus megvalósítására készült. A regiszter segítségével vált tisztázhatóvá a hepatitis C elleni új, hármas kezelésre várakozók száma és összetétele: 3000, korábban sikertelenül kezelt betegnél indokolt és lehetséges az újrakezelés, 40%-uknál a májbetegség már cirrhosis stádiumában van, és 40%-uk volt a korábbi kettős kezelésre nullreagáló. A rendszer a benyújtott IFN-alapú kezelési kérelmekhez automatikusan hozzárendeli a szakmai ajánlásban, illetve finanszírozási protokollban meghatározott prioritási indexet, ami a kezelés sürgősségének mérőszáma. Legfőbb meghatározója a fibrosis mértéke, de szerepelnek benne a betegség progressziójának mértékét, a gyógyhajlamot és speciális szempontokat tükröző összetevők is. Orv. Hetil., 2013, 154, 1151–1155.

Background: Chronic hepatitis C (CHC) patients achieving rapid virological response (RVR) on PEG-IFN/ribavirin (P/R) therapy have high chance of sustained virological response (SVR). To analyze host immunological factors associated with RVR, viral kinetics, phenotype distribution and Th1/Th2 cytokine production by peripheral blood mononuclear cells (PBMC) were studied prior to and during P/R therapy. Methods: TNF-α, IFN-γ, IL-2, IL-6, IL-4 and IL-10 production by PBMC were measured after Toll-like receptor 4 (TLR-4) or phorbol myristate acetate/Ionomycin stimulation in 20 healthy controls and in 50 CHC patients before receiving and during P/R therapy. RVR was achieved by 14, complete early virological response (cEVR) by 19 patients and 17 patients were null-responders (NR). Results: Patients with RVR showed an increased baseline TNF-α and IL-6 production by TLR-4 activated monocytes and increased IFN-γ, decreased IL-4 and IL-10 production by lymphocytes compared to non-RVR patients. SVR was also associated with increased baseline TNF-α production and decreased IL-10 levels compared to patients who did not achieve SVR. Baseline IL-2 production was higher in cEVR compared to NR patients. Antiviral treatment increased TNF-α, IL-6 production by monocytes and IFN-γ secretion by lymphocytes and decreased IL-4 and IL-10 production by lymphocytes in cEVR compared to NR patients. Conclusion: RVR was associated with increased baseline proinflammatory cytokine production by TLR-4 stimulated monocytes and by activated lymphocytes. In null-responders and in patients who did not achieve SVR both TLR-4 sensing function and proinflammatory cytokine production were impaired, suggesting that modulation of TLR activity and controlled induction of inflammatory cytokine production may provide further therapeutic strategy for CHC patients non-responding to P/R treatment. Deposited by bulk import

Endogenous peroxidase (EPX) activity in certain cells in the gastrointestinal system interferes with immunohistochemical methods based on the horseradish peroxidase-catalyzed substrate deposition. We studied the distribution and characteristics of these cells. We also report an effective and antigen-preserving EPX blocking method, to make possible the evaluation of immunoperoxidase stainings in cryostat sections. The EPX-containing cells (EPX cells) are present in every part of the gastrointestinal tract, predominantly in the tunica propria. We identified them as eosinophil cells in May-Grünwald-Giemsa stained sections. The complete match was confirmed by different fluorescence techniques. Firstly, the EPX cells were labeled by a red fluorochrome-conjugated substrate of peroxidase enzymes, rhodamine-tyramide, whereas the eosinophil cells were labeled by the green fluorochrome, l-hydroxy-3,6,8-pyrenetrisulfonic acid, which is known to label exclusively eosinophilic granules at pH 10. Secondly, all the EPX cells reacted with a monoclonal antibody against the eosinophil peroxidase enzyme. Finally, a set of commercially available leukocyte markers was used to characterize the EPX cells colabeled by fluorochrome-tyramides. Neither macrophages nor mast cells showed EPX activity. Increased numbers and altered distribution were seen in stressed rats and in ulcerated human stomach.

Cells of the exocrine pancreas produce digestive enzymes potentially harmful to the intestinal mucosa. Dopamine has been reported to protect against mucosal injury. In looking for the source of dopamine in the small intestine, we found that the duodenal juice contains high levels of dopamine and that the pancreas itself has a high dopamine [and dihydroxyphenylalanine (dopa)] content that does not change significantly after chemical sympathectomy. Furthermore, we were able to demonstrate tyrosine hydroxylase (TH) activity in control pancreas as well as in pancreas from rats after chemical sympathectomy. Immunostaining and in situ hybridization histochemistry confirmed both the presence of TH, dopamine, and the dopamine transporter, and the mRNAs encoding TH and dopamine transporter, and the presence of both types of vesicular monoamine transporters in the exocrine cells of the pancreas. Since there are no catecholaminergic enteric ganglia in the pancreas, the above results indicate that pancreatic cells have all the characteristics of dopamine-producing cells. We suggest that the pancreas is an important source of nonneuronal dopamine in the body, and that this dopamine has a role in protecting the intestinal mucosa and suggests that dopamine D1b receptor agonists might be used to help mucosal healing in the gastrointestinal tract.

Intragastric pH-metry is widely used to evaluate the efficacy of antisecretory drugs, but statistical interpretation of the measurements has not yet been standardised.The effects of single morning (N = 9) or evening (N = 7) doses of the H2-receptor antagonist famotidine, 20 mg (QUAMATELR. Gedeon Richter, Hungary) were compared by 24-hour intragastric pH-metry in hyperacid patients, in a prospective, controlled clinicopharmacological study. Intragastric pH was repeatedly measured with or without administration of famotidine, and ¿1¿ the minute to minute median pH values were calculated.¿2¿ Both treatments significantly reduced gastric acidity according to the "traditional" parameters of the time at pHor = 3, or median pH in the first 12 hours. Famotidine treatment in the evening was more effective than in the morning (634 vs 463 min or 5.22 vs 3.10). The morning and evening treatment groups did not differ from each other in these parameters when compared on the days without famotidine. ¿3¿ After demonstration of the significant differences between the treatment vs control days, and morning vs evening administrations we applied the Pattern Recognition by Independent Multicategory Analysis (PRIMA) method to select the most sensitive parameters for evaluation of the H2-receptor antagonist drug effect. The PRIMA method was developed to determine the sensitivity of each statistical parameter analysed in a comparison of different groups (discriminating power), and to determine the separability of groups using several parameters concomitantly (separation of groups). The mean pH, the period at pHor = 3, and the duration of pH-increaseor = 1 on the day of treatment compared to the control day were found to be the most sensitive parameters both in demonstrating H2-receptor antagonist effect and in differentiation of morning and evening doses. ¿4¿ High separability of morning and evening treatment groups was achieved using these three parameters concomitantly according to the PRIMA method.This method may be of value in other clinical or clinicopharmacological trials to standardise the statistical analysis of data by selection of the most sensitive parameters for comparison of the patient groups. In subsequent studies it might also increase the sensitivity of discrimination by concomitant analysis of different parameters using the smallest appropriate number of patients.

Background/Aim: The potential role of co-infections with novel hepatitisviruses such as torque teno viruses (SENV and TTV) is not clear in HCVinfection. We determined the prevalence and clinical significance of theseagents in different forms of HCV infection. Patients: a total of 365 HCVinfected individuals have been studied. Out of them 33 were symptomfree HCV carriers with persistently normal alanine aminotransferase (ALT), 97suffered from chronic hepatitis C not treated with interferon (IFN)-basedtherapy, 48 patients (pts) had chronic hepatitis C and treated with IFN+ ribavirin (RBV) for one year, 76 pts previously treated with IFN+RBVand achieved sustained virological response (SVR) and 111 were non-responders to IFN +RBV. One hundred and eight healthy volunters served as controls for TTV studies and 40 for SENV investigations. Methods: HCVRNA was detected using Roche Cobas Amplicor Monitor 2.0 test, TTV DNA, SENV-D and SENV-H DNA by PCR method. Results: Prevalance of both SENV-D, SENV-H and TTV was higher in HCV pts than in healthy controls (SENV-D: 43.7% vs. 7.5%; SENV-H 66.6% vs. 35.0% and TTV: 77.7% vs. 18.5%, respectively). Both SENV and TTV carriers have lower serum ALT and higher HCV RNA levels than SENV negative and TTV negative pts. IFN+RBV treated pts with SVR, after the therapy showed lower frequency of SENV-D (10.5%) and TTV (3.9%) than not treated ones. HCV pts with SENV-D achieved lower SVR (33%) than SENV-D negative pts (45%). Conclusion: Torque teno viruses can be "accidental tourists" in HCV infection, and though they may interfere with HCV, their pathogenetic role in liver injury is questionable. They may be IFN (+RBV?) sensitive agents.

More than 1% of the Hungarian population is infected with hepatitis B, C, or D viruses. Since 2006 the diagnostics and therapy of these infections are carried out in treatment centers according to national guidelines – since 2010 according to financial protocols. The consensus-based guidelines for 2012 are published in this paper. The guidelines stress the importance of quick and detailed virologic evaluations, the applicability of transient elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection is pegylated interferon for 48 weeks or continuous entecavir therapy. The later must be continued for at least 6 months after hepatitis B surface antigen (HBsAg) seroconversion. Tenofovir disoproxil fumarat is not yet reimbursed by the National Health Insurance Fund. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection. Treatment naive chronic hepatitis C patients should initially receive pegylated interferon and ribavirin dual combination therapy. In genotype 1 infection if response is insufficient at 4 or 12 weeks one of the two new direct acting antivirals (boceprevir or telaprevir) should be added. The length of treatment is usually 48 weeks; in cases of extended early viral response shorter courses are recommended. Previous treatment failure patients with genotype 1 infection should receive a protease inhibitor backed triple combination therapy, mostly for 48 weeks. However, relapsers without cirrhosis and with extended rapid viral response, shorter telaprevir based combination therapy is sufficient. Drug-drug interactions as well as emergence of viral resistance are of particular importance. For genotype 2 or 3 HCV infections 24 weeks, for genotype 4 infections 24, 48 or 72 weeks of pegylated interferon plus ribavirin therapy is recommended in general. The guidelines published here become protocols when published as official publications of the Hungarian Health Authority. Orv. Hetil., 2012, 153, 375–394.

Hepatitis C virus (HCV) infection affects 2–3% of the population, approximately 170 million people worldwide, causing chronic HCV-related hepatitis with subsequent liver cirrhosis, hepatic failure, hepatocellular cancer, and liver-related mortality in a large number of patients. The gold standard therapy, pegylated interferon alpha in combination with ribavirin can eradicate hepatitis C virus infection in approx. 40% of treatment-naïve patients infected with HCV genotype G1, and only 15–20% of patients with previous treatment. Success rate is substantially improved with the development and registration of two direct acting anti-hepatitis C virus protease inhibitors (boceprevir and telaprevir) in the second decade of 21st century: combined with the standard therapy, almost three quarter of previously untreated, and more than half of previously unsuccessfully treated patients can achieve sustained viral response with protease inhibitor based triple therapies. A major barrier to successful treatment is the association of peginterferon/ribavirin therapy with frequent and sometimes serious adverse effects. In clinical trials, approximately 10–15% of treated patients discontinue peginterferon and ribavirin due to adverse events; however, in routine clinical practice, the rate of treatment discontinuation has been reported to be substantially higher. The side effects of peginterferon/ribavirin therapy affect virtually all organ systems, and addition of protease inhibitor can amplify these side effects (particularly anemia), and/or may lead to new ones (i.e., dysgeusia with boceprevir or skin rush with telaprevir). There is considerable regional and global variability in the nature and prevalence of these adverse effects as well as in the best strategies to ameliorate their impact on hepatitis C virus treatment. This article summarizes the side effects of dual and triple therapies and their management based on the labels of the drugs, on a comprehensive literature review, as well as on the recently published opinion of an international panel of experts – with the provision of providing help for the physicians treating hepatitis C virus infection to achieve the best possible success with the highest possible safety for the patients. Orv. Hetil., 2011, 152, 1997–2009.

Chronic hepatitis C virus (HCV) infection is the major etiology and the reason of chronic liver disease, liver cirrhosis, hepatic decompensation, hepatocellular cancer and liver transplantation. Less than half of patients with HCV-related chronic hepatitis achieve sustained viral clearance with current pegylated interferon and ribavirin (P+R) combination therapy. Due to the insufficient treatment success, an extended search for new, direct acting anti-HCV agents (DAAs) is ongoing, already leading to submissions of applications for marketing authorization of the protease-inhibitors boceprevir and telaprevir. Both are effective only in triple combinations with P+R. Studies demonstrate a 50% success rate advantage for triple therapies above current standards. In addition, treatment duration can be shortened, and half of the patients who failed previous therapy with P+R can be cured with triple therapies. A major concern with new DAAs is rapid development of DAA-resistant viral mutants, a reason as well as a consequence of insufficient triple therapy. Clinical studies with boceprevir and telaprevir are reviewed in this paper.

HCV infects approximately 2-3% of the global population and is a leading cause of end-stage liver disease and hepatocellular carcinoma. Treatment of HCV infection with Peg-IFN in combination with ribavirin can eradicate HCV infection in 40-90% of patients; however, a major barrier to treatment uptake and delivery is the association of this therapy with frequent and, at times, serious adverse effects. Recognition and effective management of these adverse effects are critical components of the successful treatment of chronic HCV infection. In clinical trials, approximately 10-15% of patients discontinue Peg-IFN and ribavirin therapy due to adverse effects; however, in clinical practice, the rate of treatment discontinuation has been reported to be substantially higher. The off-target effect of Peg-IFN and ribavirin impacts most, if not all, organ systems; the most common adverse effects are hematologic, dermatologic, neurologic, immunologic, gastrointestinal, pulmonary, cardiovascular, and ocular. Regional and global variability exists in the nature of these adverse effects and the strategies employed to ameliorate their impact. This article provides a comprehensive literature review that systematically describes the adverse effects of Peg-IFN-α and ribavirin on various organ systems and, more importantly, recommends consensus approaches to managing those effects.

Background Infliximab (IFX) has proven to be an effective addition to the therapeutic arsenal for refractory, fistulizing, and steroid dependent Crohn's disease (CD), with efficacy in the induction and maintenance of clinical remission of CD. Our objective in this study is to report the nationwide, multicenter experience with IFX induction therapy for CD in Hungary. Methods During a 6-year-period, beginning in 2000, a total of 363 CD patients were treated with IFX as induction therapy (5 mg/kg IFX infusions given at week 0, 2 and 6) at eleven centers in Hungary in this observational study. Data analysis included patient demographics, important disease parameters and the outcome of IFX induction therapy. Results Three hundred and sixty three patients (183 women and 180 men) were treated with IFX since 2000. Mean age was 33.5 ± 11.2 years and the mean duration of disease was 6.7 ± 6.1 years. The population included 114 patients (31.4%) with therapy-refractory CD, 195 patients (53.7%) with fistulas, 16 patients (4.4%) with both therapy-refractory CD and fistulas, and 26 patients (7.2%) with steroid dependent CD. Overall response rate was 86.2% (313/363). A higher response rate was observed in patients with shorter disease duration (p = 0.05, OR:0.54, 95%CI:0.29-0.99) and concomitant immunosuppressant therapy (p = 0.05, OR: 2.03, 95%CI:0.165-0.596). Concomitant steroid treatment did not enhance the efficacy of IFX induction therapy. Adverse events included 34 allergic reactions (9.4%), 17 delayed type hypersensitivity (4.7%), 16 infections (4.4%), and 3 malignancies (0.8%). Conclusion IFX was safe and effective treatment in this cohort of Hungarian CD patients. Based on our experience co-administration of immunosuppressant therapy is suggested in patients receiving IFX induction therapy. However, concomitant steroid treatment did not enhanced the efficacy of IFX induction therapy.

Since oxidative stress may play a pathogenetic role in chronic hepatitis C, and sustained virological response to antiviral therapy is limited in HCV1 genotype infection, a double blind study was performed in HCV1 patients treated with pegylated interferon + ribavirin, to assess the efficacy of supplementation with the antioxidant flavonoid silymarin.Thirty-two naive HCV1 positive patients with biopsy proven chronic hepatitis C, to be treated with pegylated interferon + ribavirin, have been randomized: group A): 16 patients have been given the antiviral therapy for 6-12 months plus placebo for the first 3 months; group B): 16 patients have been treated with pegylated interferon + ribavirin for 6-12 months plus silymarin, 2 x 166 mg/day, was given for 3 months. Serum alanine aminotransferase and HCV-RNA levels as well as parameters of oxidative stress such as plasma or red blood cell hemolysate, malondialdehyde, superoxide dismutase, glutathione peroxidase, catalase and myeloperoxidase were determined after 0, 1, 3, 6 and 12 months during the treatment. Sustained virological response as undetectable serum HCV RNA was evaluated 24 weeks after the end of therapy.In the silymarin group, a more rapid decrease in the malondialdehyde level as well as a marked decrease in superoxide dismutase and an increase in myeloperoxidase activity after month 12 were found, alanine aminotransferase normalized in 6/16 (vs control 9/16) cases, and sustained virological response occurred in 3/16 (vs 7/16) patients.Although silymarin supportation to antiviral therapy improved oxidative stress, it was able to affect favourably neither the alanine aminotransferase nor the sustained virological response. These contradictory findings may be related to randomization bias as patients in study group B had more negative predictors of response: they were older with higher fibrosis score and even with more severe pretreatment baseline oxidative stress. Regarding the recently published in vitro experiments with silybinin on HCV replication as well as the newest convincing clinical observations, we do suggest further studies with more than three times higher doses of silymarin in controlled trials to assess the value of this supplementation in antivirally treated HCV patients.

The outcome of HCV infection and the response to antiviral treatment depend on both viral and host factors. Host immune response contributes not only to viral control, clinical recovery and protective immunity, but also to chronic hepatitis and liver cirrhosis. Establishing immunological status and identifying pretreatment immunological factors associated with better response to therapy might be of importance in the understanding of the successful immune response and in the future of combination therapy to HCV infection.The authors delivered a review on the immunology of HCV infection and characterized the cause of impaired cellular immune response in chronic HCV infection. Natural killer (NK) cell activity, perforin and the inhibitory CD81 HCV co-receptor expression, and Th1/Th2 cytokine production of the monocytes and lymphocytes have been investigated.42 patients with chronic hepatitis C, out of them 25 being on interferon (PEG-IFN) + ribavirin (RBV) therapy, 12 sustained virological responders, 26 HCV carriers with normal transaminase values and 22 healthy controls were studied. NK cell activity, perforin and CD81 expression, the IFNgamma, TNFalpha, IL-2 (Th1) and IL-4, IL-6, IL-10 (Th2) production of LPS stimulated monocytes and PMA + ionomycine stimulated lymphocytes were measured by flow-cytometry.In patients with chronic hepatitis C we demonstrated decreased NK cell activity associated with increased CD81 expression. The perforin expression of lymphocytes was also impaired in HCV patients. The pretreatment capacity of the macrophages to produce TNFalpha was predictive for sustained virological response. This increased TNFalpha production of the monocytes counteracted the observed impaired Th1 type cytokine production of the lymphocytes. IL-10 and IL-4 production showed positive correlation with HCV RNA levels, and negative correlation with histological activity index was noted. PEG-IFN + RBV treatment increased NK activity, perforin expression, Th1 type cytokine production of thr lymphocytes and downregulated CD81 expression inducing effective cellular immune response against HCV. The author's results provide further data to understand the causes of impaired cellular immune response in chronic HCV hepatitis and may be useful in the developement of immunotherapy as an adjunctive treatment to cure patients with chronic hepatitis C.

Viral hepatitis is a problem of population health. Recent data show an estimated number of 400 million patients infected with hepatitis B and 170 million with hepatitis C virus in the world. The prevalence of HBV infected patients is estimated to 50000, the prevalence of the HCV patients to 70,000 in Hungary.The authors report the legal and occupational health aspects of viral hepatitis. The knowledge of these facts could help both the patients and doctors. This paper is on the employment, occupational restrictions of the infected patients, the legal aspects of the discrimination and the vaccination. The authors report the knowledge, rules and restrictions relating to health service employees in a separate subchapter. They call the attention to the occupational health aspects in relation to the infected patients and health service employees from the point of view of the occupational health specialist, the commissioner responsible for safeguarding the patients' interest and the specialist attending the infected patients.