[Congress of the European Association for the Study of the Liver].
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Antiviral Agents↗
Biomedical subjects
Alajos Pár
Publications and source records attributed to Alajos Pár.
[Immunology of HCV infection: the causes of impaired cellular immune response and the effect of antiviral treatment].
BACKGROUND: 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. AIMS: 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. PATIENTS AND METHODS: 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. RESULTS: 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.
Adult↗
Comprehensive regression analysis of hepatitis B virus X antigen level and anti-HBx antibody titer in the sera of patients with HBV infection.
Although the pathogenetic significance of hepatitis B virus x protein (HBxAg) in chronic hepatitis, liver cirrhosis, and primary hepatocellular carcinoma has already been studied, the comparative analyses of both the actual serum HBxAg levels and antibody production against various HBx epitopes have been examined to lesser extent. We have simultaneously investigated the relationship between antibody production (IgG and IgM) against the HBxAg fragments and HBxAg level in the sera of patients with acute (14) or chronic hepatitis (80) and symptomless carriers (12). A recently developed sandwich-type ELISA was used for the quantitative measurements of HBxAg. Overlapping recombinant and synthetic antigens were used to map the fine epitope specificities of circulating anti-HBx antibodies. In acute hepatitis, we have found high and homogenous correlation in the IgM type immune responses against all the examined HBxAg regions. Moreover, strong correlation has been observed between IgG type immune responses to a characteristic C-terminal region (C1: 79-117) and the longest fragment (X: 10-143). Moderate correlation has been found between HBxAg concentration and the IgG type anti-HBx antibody levels against C-terminus of HBxAg in patients with chronic hepatitis. In the case of symptomless carriers, there were also demonstrable associations in the immune responses against the C-terminal sequences; however, significant correlations were found for antibody production against the N-terminal region as well. The examinations show that the C-terminal sequence, responsible for transactivation, promotes an efficient IgG antibody response in all three groups of patients, whereas the negative regulator N-terminal part of the HBxAg molecule for the most part does not trigger antibody production. This suggests that the immune responses against various - biologically active - epitopes of the HBxAg may have a different role in the pathogenesis of hepatitis and may be used as prognostic markers in human HBV infections.
Amino Acid Sequence↗
Involvement of serum retinoids and Leiden mutation in patients with esophageal, gastric, liver, pancreatic, and colorectal cancers in Hungary.
AIM: To analyze the serum levels of retinoids and Leiden mutation in patients with esophageal, gastric, liver, pancreatic, and colorectal cancers. METHODS: The changes in serum levels of retinoids (vitamin A, alpha- and beta-carotene, alpha- and beta-cryptoxanthin, zeaxanthin, lutein) and Leiden mutation were measured by high liquid performance chromatography (HPLC) and polymerase chain reaction (PCR) in 107 patients (70 males/37 females) with esophageal (0/8), gastric (16/5), liver (8/7), pancreatic (6/4), and colorectal (30/21 including 9 patients suffering from in situ colon cancer) cancer. Fifty-seven healthy subjects (in matched groups) for controls of serum retinoids and 600 healthy blood donors for Leiden mutation were used. RESULTS: The serum levels of vitamin A and zeaxanthin were decreased significantly in all groups of patients with gastrointestinal (GI) tumors except for vitamin A in patients with pancreatic cancer. No changes were obtained in the serum levels of alpha- and beta-carotene, alpha- and beta-cryptoxanthin, zeaxanthin, lutein in patients with GI cancer. The prevalence of Leiden mutation significantly increased in all groups of patients with GI cancer. CONCLUSION: Retinoids (as environmental factors) are decreased significantly with increased prevalence of Leiden mutation (as a genetic factor) in patients before the clinical manifestation of histologically different (planocellular and hepatocellular carcinoma, and adenocarcinoma) GI cancer.
Adult↗
[The legal and occupational health aspects of B and C type viral hepatitis].
INTRODUCTION: 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. AIMS: 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.
Health Personnel↗
[Safety of pegylated interferon in patients with hepatitis C virus induced cirrhosis].
OBJECTIVES: The authors described their experience with the therapy with pegylated interferon and its safety in patients with hepatitis C virus (HCV) induced liver cirrhosis treated at First Department of Medicine, Medical School, University of Pécs and at Tawam Hospital, Al Ain, United Arab Emirates. PATIENTS AND METHODS: Twenty four (12 male, 12 female, average: 55.66 +/- 7. 02 years) anti-HCV and/or HCV-RNA PCR positive cirrhotic patients were examined. Liver cirrhosis was diagnosed by abdominal ultrasound and/or histological examination of liver biopsy. RESULTS: Different genotypes of HCV were detected: genotype 1 in 7 cases, genotype 2 in 1 person, genotype 3 in 3 cases. Genotype 4 was detected in 10 patients, all of them were treated out of Hungary. Thirteen of 24 patients were not treated earlier, 6 persons were non-responders to previous interferon monotherapy, pegylated interferon was administered to 5 patients because of relapse. Biochemical parameters showed improvement in 16 cases (16/24, 66.66%), but did not in 5 patients. Until now, virological response was achieved in 13 patients (13/24, 54.16%), while three patients remained HCV-PCR positive. Temporary dose reduction was needed in 13/24 cases (54.16%). Withdrawal of therapy became necessary in only 2 patients due to severe neutropenia, thrombocytopenia and/or signs of decompensation. CONCLUSIONS: Pegylated interferon treatment is well tolerated by patients with compensated liver cirrhosis (Child-Pough stage A). Frequent side-effects (half of all cases) were usually mild or moderate requiring discontinuation only in 2 of 24 patients. The incidence of neutropenia and thrombocytopenia emphasizes the need of frequent blood cell count tests and patients follow up.
Antiviral Agents↗
Sandwich type ELISA and a fluorescent cytometric microbead assay for quantitative determination of hepatitis B virus X antigen level in human sera.
The hepatitis B virus X protein (HBxAg) is responsible for severe complications of HBV infections including primary hepatocellular carcinoma. A sandwich type ELISA and a flow cytometric microbead assay for quantitative determination of serum levels of Hbx-Ag are introduced. We have previously developed monoclonal antibody families against well-conserved epitopes on HbxAg, characterized by different immunohistochemical and immunoserological techniques. Special selection of the antibody pairs provided highly sensitive and highly specific tools for quantitative immunoassay development. The resulting assays were tested on human sera (208 samples) collected from patients suffering from different clinical forms of HBV infection. The sensitivity range of the sandwich type ELISA was between 4 and 2000 ng/ml as measured on both the recombinant antigen and the sera of chronic hepatitis patients. A further flow cytometric microbead assay was established and tested in parallel with the ELISA. The quantitative results of these two immunoserological techniques were in strong correlation and they were found to be highly specific and sensitive on clinical samples. The HBxAg ELISA technique is applicable for routine clinical laboratory measurements, and our HBxAg microbead technique is recommended for complex multiparametric measurements combined with other markers.
Amino Acid Sequence↗
[Treatment of primary sclerosing cholangitis].
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Cholangitis, Sclerosing↗
[Liver fibrosis: pathophysiology, diagnosis and treatment].
The extracellular matrix deposition in the liver parenchyma is a major component of cirrhosis. A great deal of knowledge has been gathered in the past two decades regarding the regulation and dynamics of fibrogenesis, and based on these advances, a review is delivered on the pathophysiology, diagnosis and therapy of liver fibrosis. The key event in fibrogenesis is the activation of hepatic stellate cells, and in its mechanism, inflammation, oxidative stress, steatosis, cytokines, growth factors, enzymes and enzyme inhibitors play a pivotal role. The phenotypic response of activated stellate cells comprises proliferation, fibrogenesis, contractility, loss of vitamin A and matrix degradation. In the diagnosis of liver fibrosis, besides liver biopsy--as "golden standard"--recently non-invasive methods, such as imaging techniques, and mainly serum fibrosis markers and indices have widely been studied. Experimental and clinical data have proved the reversibility of fibrosis, and suggested that an effective antifibrotic treatment in the future may serve even for the prevention of cirrhosis.
Biomarkers↗
Crohn's disease is associated with polymorphism of CARD15/NOD2 gene in a Hungarian population.
Crohn's disease (CD) is commonly classified as an immune-mediated disorder, but genetic and environmental factors seem to be important in its pathogenesis. Mutations within the CARD15/NOD2 gene have been associated with CD in the Caucasian population. The aim of our work was to investigate the allele frequency and clinical impact of the three common mutations in Hungarian CD patients and healthy controls. Seventy-four CD patients and 107 controls were examined. The genotyping of the three common CARD15/NOD2 mutations (Arg702Trp, Gly908Arg, and Leu1007fsinsC) was carried out by restriction fragment length polymorphism (RFLP) and amplification refractory mutation system (ARMS) techniques. The demographic and clinical parameters were correlated with chi(2) analysis. The overall prevalence of CARD15/NOD2 mutations in the Hungarian CD patients (33.78%) was significantly higher than in healthy control individuals (16.23%) (P < 0.025). The allele frequency of the Gly908Arg mutation did not differ, but the Arg702Trp and Leu1007fsinsC mutation were more common in CD patients than in controls. The onset of CD occurs about three years earlier in CARD15/NOD2 carriers. Carriage of the Arg702Trp and Leu1007fsinsC allele within the CARD15/NOD2 gene is associated with CD. These data are in line with similar findings showing a role of the CARD15/NOD2 protein in the etiopathogenesis of CD. The genotyping of these mutations might be used to identify high-risk patients.
Adult↗
[Autoimmune hepatitis].
First the short history of the disease, then its etiopathogenesis, the role of genetic, environmental and immunologic factors are described. In the second part, the questions of diagnosis, differential diagnosis and the immunosuppressive treatment, with new therapeutic modalities and liver transplantation are discussed.
Diagnosis, Differential↗
[Viral co-infections in hepatitis C: HBV, HBV-C/HGV and TTV studies].
BACKGROUND/AIMS: The prevalence of co-infections with hepatitis B virus (HBV) and novel hepatitis viruses GBV-C (Hepatitis G virus, HGV) and TT virus (TTV) in chronic hepatitis C (HCV) infection has been studied. In patients with chronic hepatitis C and in asymptomatic healthy HCV carriers, the influence of these agents on the course of HCV infection was assessed. METHODS: a total of 110 HCV-positive individuals, among them 77 patients with chronic hepatitis C--50 of them treated with interferon (IFN)--and 33 HCV carriers with normal alanine aminotransferase have been investigated. HBV-DNA, HGV RNA and TTV DNA were detected by PCR, to determine HBsAg and anti-HBc ELISA technic has been used. RESULTS: In the healthy population, the prevalence of anti-HCV was 0.3%, HBsAg 0.09%, anti-HBc 2.5%, HGV RNA 8.0% and TTV DNA 18.5%, respectively. In chronic hepatitis C HBsAg (accompanied with HBV-DNA) occurred in 1.29%, anti-HBc 25.97%, HGV RNA in 9.09% and TTV DNA in 40.25% of cases. In IFN-treated patients with sustained remission, the frequency of TTV was 20% vs. 45.7% found in non-responders. Among asymptomatic HCV-carriers, the prevalence of anti-HBc was 27.27%, HGV RNA 9.09% and TTV DNA 75.7% respectively. CONCLUSIONS: Neither previous HBV infection, nor HGV RNA and TTV DNA had apparent effect on the course of chronic HCV infection. TTV was detected with the lowest frequency in persons with sustained remission due to IFN, suggesting antiviral effect of IFN on TTV.
Adolescent↗
A long-term follow-up of five patients with atresia of the common bile duct.
BACKGROUND/PURPOSE: Description of the long-term follow-up of 5 patients operated on for atresia of the common bile duct. METHODS: During a 25-year period (1960 to 1985) 45 infants underwent surgical exploration for biliary atresia (BA), of which, 5 (11.1%) were found to have atresia of the common bile duct. The children were followed up into adult life by pediatric surgeons, pediatricians, and later, adult hepatologists with the range of 19 to 36 years. Liver function tests, histology, complications, and somatic development (including sexual maturation and mental development) were obtained continuously. RESULTS: Liver function test results were normal in all but 1 patient. Repeated ultrasound scan and postoperative liver biopsies were normal in 2 patients and moderately and mildly abnormal in 3 patients, respectively, suggesting hepatic fibrosis. HIDA hepatic scans in all but 1 patient showed prompt uptake by the liver with passage into the bowel within 30 minutes. Endoscopic retrograde cholangiography (ERCP; 1 patient) and duodenography (4 patients) showed, at most, mild reflux of contrast material into the extra- or intrahepatic bile ducts. One patient with cholecysto-duodenostomy had 3 episodes of clinically proven ascending cholangitis. All 5 patients had normal physical growth and mental development, they are all age-appropriate schooled, and they are working and living a normal life. CONCLUSIONS: Long-term favorable outcome has been suggested to be more influenced by anatomic and biological features rather than the surgical correction. The hypothesis is supported that BA is not a static congenital malformation but a progressive inflammatory panductular obliterative disease of the bile ducts starting in the antenatal period, which might cease, either early at birth or any time in infancy. The destructive inflammatory process might involve only the distal part of the extrahepatic bile duct causing obstruction and leaving the proximal ducts patent.
Adult↗
Paradoxical alteration of acute-phase protein levels in patients with chronic hepatitis C treated with IFN-alpha2b.
Previously we observed elevation of the serum concentration of two acute-phase protein (AFP) complement components (C9 and C1-inhibitor) in patients with chronic hepatitis C who responded (R) to IFN-alpha therapy, but not in non-responders (NR). In the present study we investigated the effect of high-dose IFN-alpha therapy on serum concentrations of two positive [orosomucoid (OROSO) and C-reactive protein (CRP)] and two negative [transferrin (TF) and fetuin/alpha2HS-glycoprotein (AHSG)] AFP in an outpatient setting. We investigated blood samples of 40 patients with chronic hepatitis C at the onset and at the end of a 3-month treatment with high-dose IFN-alpha2b (5 MIU/day for 6 weeks, followed by 5 MIU t.i.w.) and of 52 healthy individuals. Serum concentrations of OROSO, TF and AHSG were measured by radial immunodiffusion; CRP levels were determined by immunotubridimetry. Compared to controls, patients with chronic hepatitis C had significantly lower OROSO and CRP, and higher AHSG levels. By the end of treatment, OROSO concentration increased in R (P = 0.0054), but not in NR patients. In contrast, TF levels decreased in R (P = 0.0040), but did not change in NR patients. Similarly, in R patients, AHSG levels tended to decrease (P = 0.0942) following IFN-alpha treatment. We conclude that the acute-phase reaction is suppressed in patients with chronic hepatitis C that may be potentially related to the responsiveness to IFN-alpha therapy.
Acute-Phase Proteins↗
Hemochromatosis (HFE) gene mutations and hepatitis C virus infection as risk factors for porphyria cutanea tarda in Hungarian patients.
AIM: It is not clear whether the mutations in hemochromatosis (HFE) gene and hepatitis C virus (HCV) infection act independently in the pathogenesis of porphyria cutanea tarda (PCT). The prevalence of both risk factors varies greatly in different parts of the world. PCT patients from Hungary were evaluated to assess both factors. METHODS: The prevalence of C282Y and H63D mutations in the HFE gene was determined in 50 PCT patients and compared with the reported control frequencies. Furthermore, the presence of HCV infection was determined and related to the patients' HFE gene status. RESULTS: The C282Y mutation was found in 8/50 cases (three homozygotes and five heterozygotes), with an 11% allele frequency (vs. 3.8% control) (P<0.05). Seventeen patients were heterozygous, one was homozygous for the H63D mutation, allele frequency 19%, which did not differ significantly from the reported control prevalence of 12.3%. Twenty-two patients (44%) were HCV-RNA positive; six out of them were heterozygous for H63D mutation, one only for the C282Y mutation and one was compound heterozygous for both mutations. CONCLUSION: HCV infection and HFE C282Y mutation may probably be independent predisposing factors for development of PCT in Hungarian patients.
Adult↗
[Treatment if acute hepatic failure].
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Brain Edema↗
[Activation of the nuclear factor kappa B--key role in oncogenesis? Chronic hepatitis C virus infection and lymphomagenesis].
INTRODUCTION: Hepatitis C virus (HCV) infection may have an etiopathogenic role in development of B-cell non-Hodgkin lymphoma (NHL). Antiapoptotic effect of the HCV may display via activation of nuclear factor kappa B (NF-kappa B) transcription factor and can lead to development of carcinoma. AIMS: 1. Activated NF-kappa B was examined in peripheral blood lymphocytes of patients with HCV infection or NHL, and HCV positive B-cell NHL. 2. NF-kappa B was detected in liver biopsies of patients with HCV positive hepatocellular carcinoma (HCC) and in lymphnodes of patients with HCV positive NHL. PATIENTS AND METHODS: 1. Fifteen patients with chronic HCV infection, 13 patients with B-cell NHL (among them 4 HCV positive) and 10 healthy subjects were examined for the activity of NF-kappa B using electrophoretic mobility shift assay (EMSA). 2. Immunohistochemistry was performed in 8 liver biopsies from HCV positive patients and 2 HCC patients (1 HCV positive and 1 HCV negative) and 2 B-cell NHL patients (1 HCV positive and 1 HCV negative). RESULTS: 1. In the HCV negative control samples there was no shift detected, but we found NF-kappa B specific oligonucleotide-protein complexes in the lymphocyte extracts from all HCV positive patients and 10/13 (76.92%) in B-cell NHL. 2. NF-kappa B was detectable in 7/8 cases in liver biopsies from HCV positive patients. Strong reaction was detected in nuclei in HCV positive HCC and NHL patients (no reaction in HCV negative biopsies). CONCLUSIONS: NF-kappa B activation was justified in both diseases, which can connect the development of both HCV infection and B-cell NHL. This factor activation may have role in hepato- and lymphomagenesis.
Adult↗
Serum anti-cholesterol antibodies in chronic hepatitis-C patients during IFN-alpha-2b treatment.
Previously we detected more than 3 times higher anti-cholesterol antibody (ACHA) levels in HIV positive patients compared to healthy individuals, however, this level significantly decreased during highly active anti-retroviral therapy (HAART). In our present study we examined whether these findings could also be detected in patients with chronic hepatitis C (CHC). We calculated the correlation between the ACHA levels and the C5b-9 complement activation product. 39 patients with CHC were treated with IFN-alpha-2b (Schering-Plough) 5 MU daily for 6 weeks, followed by 5 MU TIW. Serum levels of ACHA and complement activation products were measured with ELISA. Serum HCV RNA was measured by a highly sensitive branched DNA technique before and 3, 6 and 12 months after the beginning of IFN-alpha-2b therapy. 52 healthy persons served as controls. At the onset of treatment ACHA level was significantly (p = 0.0062) higher in patients (40 (24-69) AU/ml) (median (interquartile range)) than in control sera (26 (20-35) AU/ml). In the 26 responder patients ACHA levels decreased to the normal level during the therapy, but no change was observed in the 13 non-responders. In patients with a sustained response ACHA levels remained low till the end of the 12 months IFN treatment. ACHA levels were significantly (p = 0.0422) higher in the patients with low (< 4.0 mmol/l) than in those with normal (> or = 4.0 mmol/l) cholesterol concentrations. The ACHA level before the therapy strongly correlated (r = 0.5499, p = 0.0014) with C5b-9 serum levels. ACHA levels are elevated in CHC, but this elevation is not as high as in HIV. Decrease of viral load by IFN-alpha-2b treatment in the responders results in normalization of ACHA concentration. High ACHA levels in patients with low serum cholesterol concentration suggest that high ACHA levels may contribute to the decrease in cholesterol levels. The correlation between the ACHA and C5b-9 levels indicate, that the ACHA may play a role in the complement activation in CHC.
Adult↗