Klara Werling - Academia.edu (original) (raw)
Papers by Klara Werling
Orvosi Hetilap, 2011
Autophagy is a self-digestion process that plays an important role in the development, differenti... more Autophagy is a self-digestion process that plays an important role in the development, differentiation and homeostasis of cells, helping their survival during starvation and hypoxia. Accumulated mutant proteins in the endoplasmic reticulum can be degraded by autophagy in alpha-1 antitrypsin deficiency. Hepatitis C and B virus may exploit the autophagy pathway to escape the innate immune response and to promote their own replication. Autophagy is decreased in response to chronic alcohol consumption, likely due to a decrease in 5'-adenosine monophosphate-activated protein kinase, increase in mTOR activity and due to an alteration in vesicle transport in hepatocytes. In obesity and alcoholic liver disease the decreased function of autophagy causes formation of Mallory-Denk bodies and cell death. The deficient autophagy can contribute to liver steatosis, to endoplasmic reticulum stress, and to progression of liver disease. Autophagy defect in hepatocellular carcinoma suggests that it can serve a tumor-suppressor function. The autophagy protein Beclin-1 levels have prognostic significance in liver tumors. Understanding of the molecular mechanism and the role of autophagy may lead to more effective therapeutic strategies in liver diseases in the future.
Orvosi hetilap, Jan 9, 2006
The combination of pegilált interferon plus ribavirin is significantly more effective than conven... more The combination of pegilált interferon plus ribavirin is significantly more effective than conventional interferon plus ribavirin, and is thus the current therapy of choice for patients with chronic hepatitis C. Forty-eight weeks of treatment with combination of pegilált interferon plus ribavirin has produced overall sustained virologic response 54-56% in patients with chronic hepatitis C. This article summarize the new therapy of chronic hepatitis C, the antiviral therapy of hepatitis C virus patients with normal aminotransferase levels, the therapy in patients with compensated cirrhosis and who were nonresponders to previous combination therapy, the effect of antiviral therapy on necroinflammation and fibrosis, and the favourable effect of haemopoetic growth factors on results of antiviral therapy. A substantial proportion of patients with chronic hepatitis C have persistently normal alanin-aminotransferase levels. Many studies have indeed provided evidence that although the major...
Gastroenterology & hepatology, 2011
Gastroenterology, 2000
Hepatitis C virus infection may act as a cofactor by inducing chronic hepatitis and cirrhosis, pl... more Hepatitis C virus infection may act as a cofactor by inducing chronic hepatitis and cirrhosis, playing a promoting role in the multistep process of hepatocarcinogenesis by maintaining liver inflammation, hepatocyte necrosis and regeneration. The aim of this study was to measure the DNA ploidy and cell proliferation of hepatocytes in patients with chronic hepatitis C. Hepatocyte nucleus suspension was analyzed from 45 patients with chronic hepatitis C and from 27 patients with chronic hepatitis non-C. The histopathological pattern of chronic hepatitis samples/grade, stage/was investigated. A significantly lower cyclin A protein expression and cytometrically measured S-phase fraction was observed in chronic hepatitis C as compared to chronic hepatitis non-C, representing suppressed cell proliferation of virus infected cells. In the chronic hepatitis C groups, the S-phase fraction depression was moderate, the grade of inflammation and cyclin A protein expression were also decreased, mainly in the severe grade group. In chronic hepatitis non-C, the number of cyclin A staining-positive cells increased parallel with severity of the inflammation. In addition, the HCV infection caused a near diploid minimally aneuploid cellular DNA content in the cases of moderate and severe histological groups. In contrast, the cellular DNA content was consequently diploid-independent of histological grades in chronic hepatitis non-C. Our results suggest that in chronic viral hepatitis C, the hepatocyte proliferation is suppressed parallel with the degree of inflammation, while the DNA content becomes aneuploid. The aneuploidy is a sign of genetic instability, predisposing the affected cells to unbalanced chromosomal abnormality which finally leads to malignant transformation.
Orvosi Hetilap, Mar 13, 2015
Infection caused by Echinococcus multilocularis is a rare helminthiasis, human cases have not bee... more Infection caused by Echinococcus multilocularis is a rare helminthiasis, human cases have not been diagnosed in Hungary until now. The endemic region is Central Europe; the occurrence of this infection has been reported from most of the neighbouring countries; however, E. multilocularis has been found in the red fox population in Hungary. Summarizing the recent knowledge concerning epidemiological, clinical patterns and therapeutic options, the authors describe the first Hungarian case of alveolar echinococcosis. In the presence of appropriate clinical findings, the possibility of this rare infection has to be considered in the differential diagnosis of infiltrative hepatic lesions.
Pathol Oncol Res, 2010
Hepatic steatosis seems a frequent histological alteration seen in chronic hepatitis C virus infe... more Hepatic steatosis seems a frequent histological alteration seen in chronic hepatitis C virus infected patients. There is still a lot to learn about the exact mechanism of effect of liver steatosis and its influence on the progression of liver diseases. Our study involved 96 chronic hepatitis C genotype 1 infected Hungarian patients who received pegylated interferon and ribavirin treatment for the first time. Degree of steatosis, viral and host factors influencing its development and its effect on the efficiency of antiviral treatment were determined. In 61 (64%) of patients the liver tissue showed varying degree of steatosis, which did not show relationship with level of alcohol consumption (p=0.5792), diabetes mellitus (p=0.5925) or body mass index (p=0.9685) in type 1 chronic hepatitis C patients. Degree of steatosis and virus titer showed strong relationship (OR=2.1). Significant relationship was also found between degree of hepatic steatosis and stage (p=0.0119), as well as between therapeutic response to combined pegylated interferon + ribavirin treatment and steatosis (p=0.0012). Our results demonstrated that steatosis has clinical significance in hepatitis C virus genotype 1 infected patients.
Orvosi Hetilap, 2015
Approximately 70.000 people are infected with hepatitis C virus in Hungary, more than half of who... more Approximately 70.000 people are infected with hepatitis C virus in Hungary, more than half of whom 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 on one hand. From socioeconomic aspect, this could also prevent further spread of the virus as well as reduce substantially long term financial burden of related morbidity. Available since 2003 in Hungary, pegylated interferon + ribavirin dual therapy 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 virologic 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 antiviral interferon-free combination therapies have been registered for the treatment of chronic hepatitis C, with a potential efficacy over 90% and typical 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 (eleastography 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 tharpy 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 virologic 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. Orv. Hetil., 2015, 156(Suppl. 2), 3-24.
Orvosi Hetilap
Apart from inflammatory reaction, the death of hepatocytes is also a characteristic of chronic he... more Apart from inflammatory reaction, the death of hepatocytes is also a characteristic of chronic hepatitis. Necroinflammation is followed by compensatory proliferation, which plays a rather important role in maintaining the liver function. Authors studied the DNA content of hepatocytes in patients with chronic hepatitis C, and determined the ratio of hepatocytes in phases G1, S and G2 to determine the hepatocyte proliferation and regeneration capacity of the liver. Liver biopsy samples were taken from 23 patients with chronic hepatitis C and from 16 with chronic hepatitis with non viral origin, from which nuclear suspension counts were done based on the histological slides. A total of 16 normal liver tissue samples served as control. The DNA index, G1, S, G2 and polyploid fraction were determined using the DNACE (Digital Image Analyzer for Nuclear Deoxyribonucleic Acid Content Estimation, KFKI/NIO, Hungary) digital imaging process. The DNA index was found to be significantly higher in the chronic hepatitis C than in the non-C group, with the verification of aneuploidy (DI > 1.10). The chronic non-C hepatitis cases showed lower G1 (88 +/- 6) and higher S (7.8 +/- 6.6) fractions. In comparison to the normal liver tissues, the chronic hepatitis C cases also revealed a significantly (p < 0.05) lower G1 (91 +/- 5) and a higher S (5.4 +/- 3.6) fraction, though staying behind the values found for the non-viral group. The deviation can be explained by the presentation of the HCV proliferation inhibitory effect. The polyploid cell fraction revealed a significantly higher value in the chronic non-viral cases as compared to the C virus group, reflecting on the decreased regeneration capacity of the liver. When comparing the HCV groups, significant differences were found between the mild and moderate cases in respect to the G1 and G2 fractions. At the same time, the moderate and severe cases showed statistical deviation regarding the DNA index. Chronic hepatitis C virus infection reduces the proliferation of hepatocytes and the regeneration capacity of the liver. The aneuploid DNA index reflects on genetic instability, which could be the basis of the malignant transformation of the cells.
Adverse drug reactions and toxicological reviews
The haemopoietic growth factors are relatively new additions to the treatment of drug-induced bon... more The haemopoietic growth factors are relatively new additions to the treatment of drug-induced bone marrow suppression. Treatment with growth factors may induce primitive cells to enter into cell cycle. In clinical practice they have beneficial effects on the neutropenia following cytotoxic chemotherapy, bone marrow transplantation, and it may be effective in severe chronic neutropenia by cause drugs. One of the classes of drugs which cause serious agranulocytosis are the antithyroid drugs. A thyrotoxic patient with methimazole-induced agranulocytosis was treated with recombinant human granulocyte-monocyte colony-stimulating factor (rHu GM-CSF). Seven days following treatment with daily subcutaneous injection of 270 micrograms rHu GM-CSF combined with antibiotics and glucocorticosteroids, granulocytes reappeared in the peripheral blood and the sepsis resolved. No side effects of the treatment were observed. The combination of rHu GM-CSF and glucocorticosteroids was successful in restoring normal granulocyte count.
Orvosi Hetilap
The authors treated a patient with methimazol (Metothyrin)-induced agranulocytosis with human rec... more The authors treated a patient with methimazol (Metothyrin)-induced agranulocytosis with human recombinant granulocyte-macrophage colony stimulating factor (GM-CSF). On day seven, after combined antibiotics, corticosteroid and at a dose of 270 ug daily subcutaneous GM-CSF therapy the septic state of the patients rapidly cured and the leucocytes reached the peripheric blood. No side effects were found. The publication of this case history might help to determine the place of human GM-CSF-s therapy in the treatment of agranulocytosis of different origin.
World journal of gastroenterology : WJG, Jan 7, 2015
To investigate whether expression of selected miRNAs obtained from fibrotic liver biopsies correl... more To investigate whether expression of selected miRNAs obtained from fibrotic liver biopsies correlate with fibrosis stage. Altogether, 52 patients were enrolled in the study representing various etiologic backgrounds of fibrosis: 24 cases with chronic hepatitis infections (types B, C), 19 with autoimmune liver diseases (autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, overlapping syndrome cases), and 9 of mixed etiology (alcoholic and nonalcoholic steatosis, cryptogenic cases). Severity of fibrosis was determined by both histologic staging using the METAVIR scoring system and noninvasive transient elastography. Following RNA isolation, expression levels of miR-21, miR-122, miR-214, miR-221, miR-222, and miR-224 were determined using TaqMan MicroRNA Assays applying miR-140 as the reference. Selection of miRNAs was based on their characteristic up- or downregulation observed in hepatocellular carcinoma. Relative expression of miRNAs was correlated with f...
PLOS ONE, 2015
Ossabaw miniature swine when fed a diet high in fructose, saturated fat and cholesterol (NASH die... more Ossabaw miniature swine when fed a diet high in fructose, saturated fat and cholesterol (NASH diet) develop metabolic syndrome and nonalcoholic steatohepatitis (NASH) characterized by liver injury and fibrosis. This study was conducted to further characterize the development of NASH in this large animal model. Ossabaw swine were fed standard chow (control group; n = 6) or NASH diet (n = 6) for 24 weeks. Blood and liver tissue were collected and liver histology were characterized at 0, 8, 16 and 24 weeks of dietary intervention. Hepatic apoptosis and lipid levels were assessed at week 24. The NASH diet group developed metabolic syndrome and progressive histologic features of NASH including: (a) hepatocyte ballooning at 8 weeks which progressed to extensive ballooning (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;90% hepatocytes), (b) hepatic fibrosis at week 16, which progressed to moderate fibrosis, and (c) Kupffer cell accumulation with vacuolization at 8 weeks which progressed through week 24. The NASH diet group showed increased hepatocyte apoptosis that correlated with hepatic total and free cholesterol and free fatty acids, but not esterified cholesterol or triglycerides. This report further characterizes the progression of diet-induced NASH in the Ossabaw swine model. In Ossabaw swine fed the NASH diet: (a) hepatocyte injury and fibrosis can occur without macrovesicular steatosis or excess triglyceride accumulation; (b) hepatocyte ballooning generally precedes the development of fibrosis; (c) there is increased hepatocyte apoptosis, and it is correlated more significantly with hepatic free cholesterol than hepatic free fatty acids and had no correlation with hepatic triglycerides.
Orvosi hetilap, Jan 30, 1987
Orvosi hetilap, Jan 12, 1989
Two cases of Richter's syndrome were observed by the authors between April and August 1987. T... more Two cases of Richter's syndrome were observed by the authors between April and August 1987. The patients were treated previously because of chronic lymphoid leukemia. The histological findings indicated in both cases immunoblast transformation of CLL. The patients were non-respondent to intensive chemotherapy and died within a short time.
Orvosi Hetilap, 2015
Diagnosis and treatment of hepatitis B and D virus infections mean that the patient is able to ma... more 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 2015, 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. Orv. Hetil., 2015, 156(Suppl. 1), 25-35.
Pathology & Oncology Research, 2009
Hepatic steatosis seems a frequent histological alteration seen in chronic hepatitis C virus infe... more Hepatic steatosis seems a frequent histological alteration seen in chronic hepatitis C virus infected patients. There is still a lot to learn about the exact mechanism of effect of liver steatosis and its influence on the progression of liver diseases. Our study involved 96 chronic hepatitis C genotype 1 infected Hungarian patients who received pegylated interferon and ribavirin treatment for the first time. Degree of steatosis, viral and host factors influencing its development and its effect on the efficiency of antiviral treatment were determined. In 61 (64%) of patients the liver tissue showed varying degree of steatosis, which did not show relationship with level of alcohol consumption (p=0.5792), diabetes mellitus (p=0.5925) or body mass index (p=0.9685) in type 1 chronic hepatitis C patients. Degree of steatosis and virus titer showed strong relationship (OR=2.1). Significant relationship was also found between degree of hepatic steatosis and stage (p=0.0119), as well as between therapeutic response to combined pegylated interferon + ribavirin treatment and steatosis (p=0.0012). Our results demonstrated that steatosis has clinical significance in hepatitis C virus genotype 1 infected patients.
Journal of Hepatology, 1998
Different isdates of hepatitis C virus (HCV) show nuclectide genomic sequence variability distrib... more Different isdates of hepatitis C virus (HCV) show nuclectide genomic sequence variability distributed throughout the genome. The effect of this variability on the seroIogicaJ diagnc&s of HCV by enzyme immunoassay remains poorly defined The aim of this &J& was to compare the reactivitv of 73 different HCV isolates tvoed bv sewence anaIvsis from patients'with chronic hepcrtitis C with their &lo&d Activity in t&e third generation screening, one second generation screeting and three confirmatory assays. Methods : Seventy three anti-HCV positive patients (40 males and 33 females) with HCV vireamia and histologically proven chronic hepatitis C were studied. HCV isolates were detenninated by RT-PCR and sequencing in NS5B regionof the gemnne. Isolates were: sixteen la, sixteen lb, one lc, three 2a, three 2b, four 2c, two 2d, seventeen 3a. three 4a, one 4c. one 4g, three 5a, one 6. The 73 sera were tested for three third generation and ccaIirmatory test (Ortho third ~neration EJA and RIBA, Abbztt third ~neration HAS IMX, Axym and M&ix, Pasteur second generation EIA and-Dzciscan). Beyllls
Orvosi Hetilap, 2011
Autophagy is a self-digestion process that plays an important role in the development, differenti... more Autophagy is a self-digestion process that plays an important role in the development, differentiation and homeostasis of cells, helping their survival during starvation and hypoxia. Accumulated mutant proteins in the endoplasmic reticulum can be degraded by autophagy in alpha-1 antitrypsin deficiency. Hepatitis C and B virus may exploit the autophagy pathway to escape the innate immune response and to promote their own replication. Autophagy is decreased in response to chronic alcohol consumption, likely due to a decrease in 5&amp;amp;amp;#39;-adenosine monophosphate-activated protein kinase, increase in mTOR activity and due to an alteration in vesicle transport in hepatocytes. In obesity and alcoholic liver disease the decreased function of autophagy causes formation of Mallory-Denk bodies and cell death. The deficient autophagy can contribute to liver steatosis, to endoplasmic reticulum stress, and to progression of liver disease. Autophagy defect in hepatocellular carcinoma suggests that it can serve a tumor-suppressor function. The autophagy protein Beclin-1 levels have prognostic significance in liver tumors. Understanding of the molecular mechanism and the role of autophagy may lead to more effective therapeutic strategies in liver diseases in the future.
Orvosi hetilap, Jan 9, 2006
The combination of pegilált interferon plus ribavirin is significantly more effective than conven... more The combination of pegilált interferon plus ribavirin is significantly more effective than conventional interferon plus ribavirin, and is thus the current therapy of choice for patients with chronic hepatitis C. Forty-eight weeks of treatment with combination of pegilált interferon plus ribavirin has produced overall sustained virologic response 54-56% in patients with chronic hepatitis C. This article summarize the new therapy of chronic hepatitis C, the antiviral therapy of hepatitis C virus patients with normal aminotransferase levels, the therapy in patients with compensated cirrhosis and who were nonresponders to previous combination therapy, the effect of antiviral therapy on necroinflammation and fibrosis, and the favourable effect of haemopoetic growth factors on results of antiviral therapy. A substantial proportion of patients with chronic hepatitis C have persistently normal alanin-aminotransferase levels. Many studies have indeed provided evidence that although the major...
Gastroenterology & hepatology, 2011
Gastroenterology, 2000
Hepatitis C virus infection may act as a cofactor by inducing chronic hepatitis and cirrhosis, pl... more Hepatitis C virus infection may act as a cofactor by inducing chronic hepatitis and cirrhosis, playing a promoting role in the multistep process of hepatocarcinogenesis by maintaining liver inflammation, hepatocyte necrosis and regeneration. The aim of this study was to measure the DNA ploidy and cell proliferation of hepatocytes in patients with chronic hepatitis C. Hepatocyte nucleus suspension was analyzed from 45 patients with chronic hepatitis C and from 27 patients with chronic hepatitis non-C. The histopathological pattern of chronic hepatitis samples/grade, stage/was investigated. A significantly lower cyclin A protein expression and cytometrically measured S-phase fraction was observed in chronic hepatitis C as compared to chronic hepatitis non-C, representing suppressed cell proliferation of virus infected cells. In the chronic hepatitis C groups, the S-phase fraction depression was moderate, the grade of inflammation and cyclin A protein expression were also decreased, mainly in the severe grade group. In chronic hepatitis non-C, the number of cyclin A staining-positive cells increased parallel with severity of the inflammation. In addition, the HCV infection caused a near diploid minimally aneuploid cellular DNA content in the cases of moderate and severe histological groups. In contrast, the cellular DNA content was consequently diploid-independent of histological grades in chronic hepatitis non-C. Our results suggest that in chronic viral hepatitis C, the hepatocyte proliferation is suppressed parallel with the degree of inflammation, while the DNA content becomes aneuploid. The aneuploidy is a sign of genetic instability, predisposing the affected cells to unbalanced chromosomal abnormality which finally leads to malignant transformation.
Orvosi Hetilap, Mar 13, 2015
Infection caused by Echinococcus multilocularis is a rare helminthiasis, human cases have not bee... more Infection caused by Echinococcus multilocularis is a rare helminthiasis, human cases have not been diagnosed in Hungary until now. The endemic region is Central Europe; the occurrence of this infection has been reported from most of the neighbouring countries; however, E. multilocularis has been found in the red fox population in Hungary. Summarizing the recent knowledge concerning epidemiological, clinical patterns and therapeutic options, the authors describe the first Hungarian case of alveolar echinococcosis. In the presence of appropriate clinical findings, the possibility of this rare infection has to be considered in the differential diagnosis of infiltrative hepatic lesions.
Pathol Oncol Res, 2010
Hepatic steatosis seems a frequent histological alteration seen in chronic hepatitis C virus infe... more Hepatic steatosis seems a frequent histological alteration seen in chronic hepatitis C virus infected patients. There is still a lot to learn about the exact mechanism of effect of liver steatosis and its influence on the progression of liver diseases. Our study involved 96 chronic hepatitis C genotype 1 infected Hungarian patients who received pegylated interferon and ribavirin treatment for the first time. Degree of steatosis, viral and host factors influencing its development and its effect on the efficiency of antiviral treatment were determined. In 61 (64%) of patients the liver tissue showed varying degree of steatosis, which did not show relationship with level of alcohol consumption (p=0.5792), diabetes mellitus (p=0.5925) or body mass index (p=0.9685) in type 1 chronic hepatitis C patients. Degree of steatosis and virus titer showed strong relationship (OR=2.1). Significant relationship was also found between degree of hepatic steatosis and stage (p=0.0119), as well as between therapeutic response to combined pegylated interferon + ribavirin treatment and steatosis (p=0.0012). Our results demonstrated that steatosis has clinical significance in hepatitis C virus genotype 1 infected patients.
Orvosi Hetilap, 2015
Approximately 70.000 people are infected with hepatitis C virus in Hungary, more than half of who... more Approximately 70.000 people are infected with hepatitis C virus in Hungary, more than half of whom 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 on one hand. From socioeconomic aspect, this could also prevent further spread of the virus as well as reduce substantially long term financial burden of related morbidity. Available since 2003 in Hungary, pegylated interferon + ribavirin dual therapy 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 virologic 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 antiviral interferon-free combination therapies have been registered for the treatment of chronic hepatitis C, with a potential efficacy over 90% and typical 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 (eleastography 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 tharpy 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 virologic 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. Orv. Hetil., 2015, 156(Suppl. 2), 3-24.
Orvosi Hetilap
Apart from inflammatory reaction, the death of hepatocytes is also a characteristic of chronic he... more Apart from inflammatory reaction, the death of hepatocytes is also a characteristic of chronic hepatitis. Necroinflammation is followed by compensatory proliferation, which plays a rather important role in maintaining the liver function. Authors studied the DNA content of hepatocytes in patients with chronic hepatitis C, and determined the ratio of hepatocytes in phases G1, S and G2 to determine the hepatocyte proliferation and regeneration capacity of the liver. Liver biopsy samples were taken from 23 patients with chronic hepatitis C and from 16 with chronic hepatitis with non viral origin, from which nuclear suspension counts were done based on the histological slides. A total of 16 normal liver tissue samples served as control. The DNA index, G1, S, G2 and polyploid fraction were determined using the DNACE (Digital Image Analyzer for Nuclear Deoxyribonucleic Acid Content Estimation, KFKI/NIO, Hungary) digital imaging process. The DNA index was found to be significantly higher in the chronic hepatitis C than in the non-C group, with the verification of aneuploidy (DI > 1.10). The chronic non-C hepatitis cases showed lower G1 (88 +/- 6) and higher S (7.8 +/- 6.6) fractions. In comparison to the normal liver tissues, the chronic hepatitis C cases also revealed a significantly (p < 0.05) lower G1 (91 +/- 5) and a higher S (5.4 +/- 3.6) fraction, though staying behind the values found for the non-viral group. The deviation can be explained by the presentation of the HCV proliferation inhibitory effect. The polyploid cell fraction revealed a significantly higher value in the chronic non-viral cases as compared to the C virus group, reflecting on the decreased regeneration capacity of the liver. When comparing the HCV groups, significant differences were found between the mild and moderate cases in respect to the G1 and G2 fractions. At the same time, the moderate and severe cases showed statistical deviation regarding the DNA index. Chronic hepatitis C virus infection reduces the proliferation of hepatocytes and the regeneration capacity of the liver. The aneuploid DNA index reflects on genetic instability, which could be the basis of the malignant transformation of the cells.
Adverse drug reactions and toxicological reviews
The haemopoietic growth factors are relatively new additions to the treatment of drug-induced bon... more The haemopoietic growth factors are relatively new additions to the treatment of drug-induced bone marrow suppression. Treatment with growth factors may induce primitive cells to enter into cell cycle. In clinical practice they have beneficial effects on the neutropenia following cytotoxic chemotherapy, bone marrow transplantation, and it may be effective in severe chronic neutropenia by cause drugs. One of the classes of drugs which cause serious agranulocytosis are the antithyroid drugs. A thyrotoxic patient with methimazole-induced agranulocytosis was treated with recombinant human granulocyte-monocyte colony-stimulating factor (rHu GM-CSF). Seven days following treatment with daily subcutaneous injection of 270 micrograms rHu GM-CSF combined with antibiotics and glucocorticosteroids, granulocytes reappeared in the peripheral blood and the sepsis resolved. No side effects of the treatment were observed. The combination of rHu GM-CSF and glucocorticosteroids was successful in restoring normal granulocyte count.
Orvosi Hetilap
The authors treated a patient with methimazol (Metothyrin)-induced agranulocytosis with human rec... more The authors treated a patient with methimazol (Metothyrin)-induced agranulocytosis with human recombinant granulocyte-macrophage colony stimulating factor (GM-CSF). On day seven, after combined antibiotics, corticosteroid and at a dose of 270 ug daily subcutaneous GM-CSF therapy the septic state of the patients rapidly cured and the leucocytes reached the peripheric blood. No side effects were found. The publication of this case history might help to determine the place of human GM-CSF-s therapy in the treatment of agranulocytosis of different origin.
World journal of gastroenterology : WJG, Jan 7, 2015
To investigate whether expression of selected miRNAs obtained from fibrotic liver biopsies correl... more To investigate whether expression of selected miRNAs obtained from fibrotic liver biopsies correlate with fibrosis stage. Altogether, 52 patients were enrolled in the study representing various etiologic backgrounds of fibrosis: 24 cases with chronic hepatitis infections (types B, C), 19 with autoimmune liver diseases (autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, overlapping syndrome cases), and 9 of mixed etiology (alcoholic and nonalcoholic steatosis, cryptogenic cases). Severity of fibrosis was determined by both histologic staging using the METAVIR scoring system and noninvasive transient elastography. Following RNA isolation, expression levels of miR-21, miR-122, miR-214, miR-221, miR-222, and miR-224 were determined using TaqMan MicroRNA Assays applying miR-140 as the reference. Selection of miRNAs was based on their characteristic up- or downregulation observed in hepatocellular carcinoma. Relative expression of miRNAs was correlated with f...
PLOS ONE, 2015
Ossabaw miniature swine when fed a diet high in fructose, saturated fat and cholesterol (NASH die... more Ossabaw miniature swine when fed a diet high in fructose, saturated fat and cholesterol (NASH diet) develop metabolic syndrome and nonalcoholic steatohepatitis (NASH) characterized by liver injury and fibrosis. This study was conducted to further characterize the development of NASH in this large animal model. Ossabaw swine were fed standard chow (control group; n = 6) or NASH diet (n = 6) for 24 weeks. Blood and liver tissue were collected and liver histology were characterized at 0, 8, 16 and 24 weeks of dietary intervention. Hepatic apoptosis and lipid levels were assessed at week 24. The NASH diet group developed metabolic syndrome and progressive histologic features of NASH including: (a) hepatocyte ballooning at 8 weeks which progressed to extensive ballooning (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;90% hepatocytes), (b) hepatic fibrosis at week 16, which progressed to moderate fibrosis, and (c) Kupffer cell accumulation with vacuolization at 8 weeks which progressed through week 24. The NASH diet group showed increased hepatocyte apoptosis that correlated with hepatic total and free cholesterol and free fatty acids, but not esterified cholesterol or triglycerides. This report further characterizes the progression of diet-induced NASH in the Ossabaw swine model. In Ossabaw swine fed the NASH diet: (a) hepatocyte injury and fibrosis can occur without macrovesicular steatosis or excess triglyceride accumulation; (b) hepatocyte ballooning generally precedes the development of fibrosis; (c) there is increased hepatocyte apoptosis, and it is correlated more significantly with hepatic free cholesterol than hepatic free fatty acids and had no correlation with hepatic triglycerides.
Orvosi hetilap, Jan 30, 1987
Orvosi hetilap, Jan 12, 1989
Two cases of Richter's syndrome were observed by the authors between April and August 1987. T... more Two cases of Richter's syndrome were observed by the authors between April and August 1987. The patients were treated previously because of chronic lymphoid leukemia. The histological findings indicated in both cases immunoblast transformation of CLL. The patients were non-respondent to intensive chemotherapy and died within a short time.
Orvosi Hetilap, 2015
Diagnosis and treatment of hepatitis B and D virus infections mean that the patient is able to ma... more 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 2015, 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. Orv. Hetil., 2015, 156(Suppl. 1), 25-35.
Pathology & Oncology Research, 2009
Hepatic steatosis seems a frequent histological alteration seen in chronic hepatitis C virus infe... more Hepatic steatosis seems a frequent histological alteration seen in chronic hepatitis C virus infected patients. There is still a lot to learn about the exact mechanism of effect of liver steatosis and its influence on the progression of liver diseases. Our study involved 96 chronic hepatitis C genotype 1 infected Hungarian patients who received pegylated interferon and ribavirin treatment for the first time. Degree of steatosis, viral and host factors influencing its development and its effect on the efficiency of antiviral treatment were determined. In 61 (64%) of patients the liver tissue showed varying degree of steatosis, which did not show relationship with level of alcohol consumption (p=0.5792), diabetes mellitus (p=0.5925) or body mass index (p=0.9685) in type 1 chronic hepatitis C patients. Degree of steatosis and virus titer showed strong relationship (OR=2.1). Significant relationship was also found between degree of hepatic steatosis and stage (p=0.0119), as well as between therapeutic response to combined pegylated interferon + ribavirin treatment and steatosis (p=0.0012). Our results demonstrated that steatosis has clinical significance in hepatitis C virus genotype 1 infected patients.
Journal of Hepatology, 1998
Different isdates of hepatitis C virus (HCV) show nuclectide genomic sequence variability distrib... more Different isdates of hepatitis C virus (HCV) show nuclectide genomic sequence variability distributed throughout the genome. The effect of this variability on the seroIogicaJ diagnc&s of HCV by enzyme immunoassay remains poorly defined The aim of this &J& was to compare the reactivitv of 73 different HCV isolates tvoed bv sewence anaIvsis from patients'with chronic hepcrtitis C with their &lo&d Activity in t&e third generation screening, one second generation screeting and three confirmatory assays. Methods : Seventy three anti-HCV positive patients (40 males and 33 females) with HCV vireamia and histologically proven chronic hepatitis C were studied. HCV isolates were detenninated by RT-PCR and sequencing in NS5B regionof the gemnne. Isolates were: sixteen la, sixteen lb, one lc, three 2a, three 2b, four 2c, two 2d, seventeen 3a. three 4a, one 4c. one 4g, three 5a, one 6. The 73 sera were tested for three third generation and ccaIirmatory test (Ortho third ~neration EJA and RIBA, Abbztt third ~neration HAS IMX, Axym and M&ix, Pasteur second generation EIA and-Dzciscan). Beyllls