Factors affecting liver disease progression, with emphasis on the role of free radical reactions / A májbetegségek progresszióját meghatározó tényezok, különös tekintettel a szabad gyökös reakciókra.

Chronic liver disorders are the main leading cause of morbidity and mortality data. Viral infection, toxic injury, metabolic, autoimmun, storage disorders, in the case of ongoing presence of the etiological factors, could result in fibrotic remodelling in the liver. The process is complex, not fully understood in details; cells, cytokines, chemokines release, altered secretion of hepatokines, lipotoxicity, innate immun system, gut microbiom, metal ions and free radical reactions all have a role in it. Chronic liver disorders are often symptomless, diagnosed in the stage of fibrotic tissue accumulation, liver failure or hepatocellular carcinoma formation, when the prognosis is poor, treatment options are narrow. Noninvasive, properly sensitive and specific biomarkers are the targets of studies, with them the necessity of liver biopsies can be decreased, through the follow-up of processes, progression and treatment efficacy. Authors review the processes taking part in the progression of the most frequent chronic liver disorders, emphasizing the parameters of pro/antioxidant balance, and the necessity of a combined reliable biomarker. Orv Hetil. 2020; 161(35): 1441-1448.

The potential role of organic and conventional yoghurt consumption in the treatment of non-alcoholic fatty liver disease / Az ökológiai és a konvencionális joghurtfogyasztás lehetséges szerepe a nem alkoholos zsírmájbetegség kezelésében.

INTRODUCTION: Health is an important motivation for the consumption of both organic and functional foods. Organic food contains fewer pesticide residues and statistically more selected health-related compounds such as polyphenols in plant products and polyunsaturated fatty acids in milk and meat products. Recent studies suggest that the gut-liver axis plays an important role in the pathogenesis of non-alcoholic fatty liver disease, so probiotics could be a therapeutic tool. Comparing the health effects of yoghurt from organic origin with so-called conventional yoghurt is difficult, because there is no biomarker that would signal the difference with good specificity and sensitivity. AIM: The aim of this study was to investigate numerous biomarkers to evaluate the difference between yoghurt from conventional and organic origin and their health effects in NAFLD. PATIENTS AND METHOD: We performed a prospective, cohort study consisting of 37 (age = 51.73 ± 11.82, male = 21, female = 16) patients with NAFLD at the 2nd Department of Internal Medicine of the Semmelweis University, Budapest. Diagnosis of NAFLD was based on ultrasonography and the exclusion of other etiololgy. The patients were examined also with shear wave elastography to evaluate the hepatic fibrosis stage. We divided the patients randomly into two groups. The patients consumed individually daily 300 grams of yoghurt from organic (n = 21) or conventional (n = 16) origin for 8 weeks. We collected 37 routine laboratory data, measured 4 cytokines, 3 markers of the redox-homeostasis and 14 body composition values before, after, and 12 weeks after the yoghurt consumption. RESULTS: We found a mild elevation of vitamin D and a minimal reduction of LDL after the yoghurt consumption, but in the other 35 routine laboratory data there was no statistical difference. Adiponectin and leptin levels were elevated after the yoghurt consumption in the "conventional group". In contrast, we found significant decrease of adiponectin levels in the "organic group" after the treatment. Only the adiponectin tendency was different in the two groups. The induced free radical content was also statistically lower after the yoghurt consumption. In the body composition measurements, there were no significant differences. CONCLUSION: These data suggest that adiponectin could be a possible biomarker to evaluate the effectiveness of probiotic treatment in non-alcoholic fatty liver disease. Our work can serve as a basis for future studies investigating relationships between organic yoghurt consumption and health outcomes. Orv Hetil. 2020; 161(35): 1466-1474.

[Hepatitis C virus infection and hepatocarcinogenesis]. / Hepatitis C-vírus-fertozés és hepatocarcinogenesis.

Hepatitis C virus infection causes approximately 4 million new infections worldwide, and 399 000 deaths due to its complications, cirrhosis and hepatocellular carcinoma (HCC). Microenvironmental changes, chronic inflammation, oxidative stress, endoplasmic reticulum stress caused by HCV infection, via genetic and epigenetic changes can result in primary liver cancer during decades. The direct oncogenic property of HCV is wellknown. The transforming effect of four HCV proteins (core, NS3, NS4B, NS5A) has been proven. Effective antiviral therapy, sustained viral response decreases the HCV-related general and liver-related mortality. Interferon-based therapy reduces the risk of HCC development. Shorter therapy with direct acting antiviral agents (DAA) has higher efficacy, fewer side-effects. Publications have reported the unexpected effects of DAA. The authors review the articles focusing on the occurrence of HCC in connection with DAA therapies. There is a need for prospective, multicentric studies with longer follow-up to examine the risk of HCC formation. After antiviral therapy, HCC surveillance is of high importance which means abdominal ultrasound every 3-6-12 months in sustained viral response patients as well. Orv Hetil. 2019; 160(22): 846-853.

[The role of gut microbiota in chronic liver diseases, and treatment possibilities]. / A bélflóra patofiziológai jelentosége és szerepe mint terápiás célpont májbetegségekben.

The community of microorganisms in the intestine, namely gut microbiome lives in symbiosis with the host, contributing to its homeostasis and influencing it simultaneously. It can be suspected that gut microbiome plays a central role in the pathophysiology of intestinal and extraintestinal diseases: determining their development, progress and complications. Recently, intestinal microbiome has become a highlighted field of interest and important topic in research, especially in hepatology. It is in the focus of relevant research as the liver is the organ which meets nutrients, bacterial components, toxins and metabolites at first, as a filter. The evolvement of different liver diseases - just like alcoholic and non-alcoholic fatty liver disease, steatohepatitis, cirrhosis or hepatocellular carcinoma - correlates with the changed composition and activity of gut microbiome. Thus, it can be hypothesized that pre-, pro- and antibiotics could have an impact on the treatment of these diseases. In our review article, the relationship between intestinal flora and liver diseases with different etiologies as well as therapeutic possibilities are discussed. Orv Hetil. 2018; 159(36): 1465-1474.

Ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin in HCV genotype 1 infected patients who failed previous protease inhibitor therapy.

AIM OF THE STUDY: Combination of ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (3DDA±RBV) therapy is shown to be effective in HCV genotype 1 (GT1) infected patients. However, sparse data exist in patients who failed previous boceprevir or telaprevir based therapies. Real life efficacy and safety of this combination were evaluated in HCV GT1b infected patients (mostly cirrhotics) with compensated liver disease who failed previous boceprevir or telaprevir based therapies more than a year before. MATERIAL AND METHODS: Data of previous protease inhibitor failure patients, treated with 3DAA+RBV for 12 weeks (GT1b and/or non-cirrhotics) or 24 weeks (non-GT1b cirrhotics), were retrospectively collected. RESULTS: Population characteristics: boceprevir/telaprevir-failure: 82/45, GT1b: 117, cirrhotic: 111 (87.4%). SVR12/24 was observed in 103/105 patients (98.1%) of those who reached either time point. Four SAEs reported: one death due to myocardial infarction, another due to recurrent hepatocellular carcinoma after achieving SVR12, two hospitalizations (elevation of transaminases, pneumonia). Grade ≥ 3 AEs or laboratory abnormalities were reported in < 10% of patients; they were transient in all patients. No early discontinuation of drugs due to SAE has been reported. CONCLUSIONS: One year after previous failure of boceprevir or telaprevir based therapy, 12 weeks of 3DAA+RBV combination in HCV GT1b infected patients is similarly effective and safe as in those with no previous HCV therapy, even in the presence of cirrhosis. These findings might be of particular interest in settings where alternative therapies for such patients are not available or not affordable.

[Screening, diagnosis, treatment, and follow up of hepatitis C virus related liver disease. National consensus guideline in Hungary from 22 September 2017]. / A hepatitis C-vírus-fertozés szurése, diagnosztikája, antivirális terápiája, kezelés utáni gondozása. Magyar konszenzusajánlás. Érvényes: 2017. szeptember 22-tol.

The treatment of hepatitis C is based on a national consensus guideline updated six-monthly according to local availability and affordability of approved therapies through a transparent allocation system in Hungary. This updated guideline incorporates some special new aspects, including recommendations for screening, diagnostics, use and allocation of novel direct acting antiviral agents. The indication of therapy in patients with no contraindication is based on the demonstration of viral replication with consequent inflammation and/or fibrosis in the liver. Non-invasive methods (elastographies and biochemical methods) are preferred for liver fibrosis staging. The budget allocated for these patients is limited. Interferon-based or interferon-free therapies are available for the treatment. Due to their limited success rate as well as to their (sometimes severe) side-effects, the mandatory use of interferon-based therapies as first line treatment can not be accepted from the professional point of view. However, they can be used as optional therapy in treatment-naïve patients with mild disease. As of interferon-free therapies, priority is given to those with urgent need based on a pre-defined scoring system reflecting mainly the stage of the liver disease, but considering also additional factors, i.e., hepatic decompensation, other complications, activity and progression of liver disease, risk of transmission and other special issues. Approved treatments are restricted to the most cost-effective combinations based on the cost per sustained virological response value in different patient categories with consensus amongst treating physicians, the National Health Insurance Fund of Hungary and patients' organizations. Interferon-free treatments and shorter therapy durations are preferred. Orv Hetil. 2018; 159(Suppl 1): 3-23.

[Diagnosis and treatment of chronic hepatitis B and D. National consensus guideline in Hungary from 22 September 2017]. / A hepatitis B- és D-vírus-fertozés diagnosztikája, antivirális kezelése. Magyar konszenzusajánlás. Érvényes: 2017. szeptember 22-tol.

Diagnosis and treatment of hepatitis B virus (HBV) and hepatitis D virus infection mean for the patient to be able to maintain working capacity, to increase quality of life, to prevent cancer, and to 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 from 22 September 2017 set by a consensus meeting of physicians involved in the treatment of these diseases. The prevalence of HBV infection in the Hungarian general population is 0,5-0,7%. The indications of treatment are 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 a cost-effective approach, the guideline stresses 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 HBV 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. Lamivudine is no longer the first choice; patients currently taking lamivudine must switch if the 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. 2018; 159(Suppl 1): 24-37.

[Extrahepatic manifestations in chronic hepatitis C infected patients]. / Extrahepaticus manifesztációk idült hepatitis C-vírus-fertozöttekben.

The importance of chronic hepatitis C infection is significant. 3% of the World's population is infected. There is at least one extrahepatic manifestation in 50% of HCV patients, which makes the prognosis and mortality worse. The pathomechanisms included are cryoglobulin production, immunmechanisms, and direct viral effects. The authors summarize the main extrahepatic manifestations, as well as treatment possibilities. The aim is to draw attention to this colourful infection in order to improve the recognition in the era of the new effective direct antiviral agents. Orv. Hetil., 2017, 158(16), 603-612.

[Screening, diagnosis, treatment, and follow up of hepatitis C virus related liver disease. National consensus guideline in Hungary from 15 October 2016]. / A hepatitis C-vírus-fertozés szurése, diagnosztikája, antivirális terápiája, kezelés utáni gondozása. Magyar konszenzusajánlás. Érvényes: 2016. október 15-tol.

Treatment of hepatitis C is based on a national consensus guideline updated six-monthly according to local availability and affordability of approved therapies through a transparent allocation system in Hungary. This updated guideline incorporates some special new aspects, including recommendations for screening, diagnostics, use and allocation of novel direct acting antiviral agents. Indication of therapy in patients with no contraindication is based on demonstration of viral replication with consequent inflammation and/or fibrosis in the liver. Non-invasive methods (elastographies and biochemical methods) are preferred for liver fibrosis staging. The budget allocated for these patients is limited. Therefore, expensive novel direct acting antiviral combinations as first line treatment are reimbursed only, if the freely available, but less effective and more toxic pegylated interferon plus ribavirin dual therapy deemed to prone high chance of adverse events and/or low chance of cure. Priority is given to those with urgent need based on a pre-defined scoring system reflecting mainly the stage of the liver disease, but considering also additional factors, i.e., hepatic decompensation, other complications, activity and progression of liver disease, risk of transmission and other special issues. Approved treatments are restricted to the most cost-effective combinations based on the cost per sustained virological response value in different patient categories with consensus amongst treating physicians, the National Health Insurance Fund and patient's organizations. Interferon-free treatments and shorter therapy durations are preferred. Orv. Hetil., 2017, 158(Suppl. 1), 3-22.

[Diagnosis and treatment of chronic hepatitis B and D. National consensus guideline in Hungary from 15 October 2016]. / A hepatitis B- és D-vírus-fertozés diagnosztikája, antivirális kezelése. Magyar konszenzusajánlás. Érvényes: 2016. október 15-tol.

Diagnosis and treatment of HBV/HDV infection means for the patient to be able to maintain working capacity, to increase quality of life, to prevent cancer, and to prolong life expectancy, while 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 2017 set by a consensus meeting of physicians involved in the treatment of these diseases. The prevalence of HBV 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 stresses the importance of quick and detailed virologic evaluations, the applicability of 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., 2017, 158(Suppl. 1) 23-35.

A hepatitis B- és D-vírus-fertozés diagnosztikája, antivirális kezelése. Magyar konszenzusajánlás. Érvényes: 2015. szeptember 12-tol.

Diagnosis and treatment of HBV/HDV infection means for the patient to be able to maintain working capacity, to increase quality of life, to prevent cancer, and to prolong life expectancy, while 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 2016 set by a consensus meeting of physicians involved in the treatment of these diseases. The prevalence of HBV 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 stresses the importance of quick and detailed virologic evaluations, the applicability of 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 ente- cavir 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. 2) 25-36.

Hepatitis C-vírus-fertozés: diagnosztika, antivirális terápia, kezelés utáni gondozás. Magyar konszenzusajánlás. Érvényes: 2015. szeptember 12-tol.

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.

[Antioxidants--antioxidative stress: facts and questions, 2015]. / Antioxidánsok--antioxidánssokk: tények és kérdések, 2015.

In the past years great importance has been attributed to antioxidant therapy in the prevention and treatment of disorders developed in connection with oxidative stress. After initial success, undesirable effects, toxicities, and prooxidant effects of antioxidants were reported [CARET, ATBC study]. In addition, metaanalyses failed to confirm the role of antioxidant supplementation in the primary and secondary prevention. The authors review the prooxidant effects of antioxidants, and their role in cell signalling and cell process modulation. Finally, the authors summarize possible explanations why combined use of antiooxidants is more favourable.

Diagnosis, treatment, and follow-up of hepatitis C virus related liver disease. Hungarian national consensus guideline.

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. From a socioeconomic aspect, this could also prevent further spread of the virus as well as reduce substantially long term financial burden of related morbidity. 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 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 (elastography and biochemical methods) are accepted and preferred for staging liver damage (fibrosis). For initiation of treatment as well as for on-treatment decisions, 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. Orv. Hetil., 2015, 156(Suppl. 1), 3-23.

Diagnosis and treatment of chronic hepatitis B and D. Hungarian national consensus guideline.

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.

[Non-invasive assessment of fatty liver]. / A májelzsírosodás nem invazív jellemzésének lehetoségei.

As the result of various harmful effects (infectious agents, metabolic diseases, unhealthy diet, obesity, toxic agents, autoimmune processes) hepatic damage may develop, which can progress towards liver steatosis, and fibrosis as well. The most common etiological factors of liver damages are hepatitis B and C infection, alcohol consumption and non-alcoholic fatty liver disease. Liver biopsy is considered as the gold standard for the diagnosis of chronic liver diseases. Due to the dangers and complications of liver biopsy, studies are focused on non-invasive markers and radiological imaging for liver steatosis, progression of fatty liver, activity of the necroinflammation and the severity of the fibrosis. Authors review the possibilities of non-invasive assessment of liver steatosis. The statistical features of the probes (positive, negative predictive values, sensitivity, specificity) are reviewed. The role of radiological imaging is also discussed. Although the non-invasive methods discussed in this article are useful to assess liver steatosis, further studies are needed to validate to follow progression of the diseases and to control therapeutic response.

[Hepatitis C: diagnosis, anti-viral therapy, after-care. Hungarian consensus guideline]. / Hepatitis C-vírus-fertozés: diagnosztika, antivirális terápia, kezelés utáni gondozás. Magyar konszenzusajánlás.

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.

[Options for non-invasive assessment of liver fibrosis based on clinical data]. / A májfibrosis nem invazív jellemzésének lehetoségei a klinikai adatok tükrében.

Liver cirrhosis is one of the leading causes of death worldwide. Liver biopsy is considered as the gold standard for the diagnosis of chronic liver diseases. Studies have focused on non-invasive markers for liver fibrosis because of the dangers and complications of liver biopsy. The authors review the non-invasive direct as well as indirect methods for liver fibrosis assessment and present the positive and negative predictive value, sensitivity and specificity of those. Clinical utilities of transient elastography (Fibrsocan) is also reviewed. Non-invasive methods are useful in the assessment of liver fibrosis, monitoring disease progression and therapeutic response. Their accuracy can be increased by the combined or sequential use of non-invasive markers.

[Diagnosis and treatment of chronic hepatitis B and D. Hungarian national consensus guideline]. / A B- és D-vírus hepatitis diagnosztikája, antivirális kezelése. Magyar konszenzusajánlás.

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.

[IL28B CC genotype: a protective factor and predictor of the response to interferon treatment in chronic hepatitis C virus infection]. / IL28B CC genotípus: védo tényezo és az interferonválasz prediktora krónikus hepatitis-C-vírus infekcióban.

INTRODUCTION: In chronic hepatitis C-virus infection the possible role of gene variants encoding cytokines has become the focus of interest. AIM: The aim of the study was to investigate the effect of IL28B polymorphisms on the outcome of chronic hepatitis C-virus genotype 1 infection in the Hungarian population. In addition, the association between IL28B genotypes and the Th1/Th2 cytokine production of activated peripheral blood monocytes and lymphocytes was evaluated. METHOD: Total of 748 chronic hepatitis C-virus genotype 1 positive patients (365 males and 383 females, aged between 18 and 82 years; mean age, 54±10 years) were enrolled, of which 420 patients were treated with pegylated interferon plus ribavirin for 24-72 weeks. Of the 420 patients, 195 patients (46.4%) achieved sustained virological response. The IL28B rs12979860 polymorphism was determined using Custom Taqman SNP Genotyping Assays (Applied Biosystems, Life Technologies, Foster, CA, USA). For cytokine studies, tumour necrosis factor-α, interleukin-2, interferon-γ, interleukin-2 and interleukin-4 production by LPS-stimulated monocytes and PMA-ionomycine activated lymphocytes were measured from the supernatant of the cells obtained from 40 hepatitis C-virus infected patients, using FACS-CBA Becton Dickinson test. The cytokine levels were compared in patients with different (CC, CT, TT) IL28B genotypes. RESULTS: The IL28B rs12979860 CC genotype occurred in lower frequency in hepatitis C-virus infected patients than in healthy controls (26.1% vs 51.4%, OR 0.333, p<0.001). Patients carried the T allele with higher frequency than controls (73.9%, vs 48.6%, OR 3.003, p<0.001). Pegylated interferon plus ribavirin treated patients with the IL28B CC genotype achieved higher sustained virological response rate than those with the CT genotype (58.6% vs 40.8%, OR 2.057, p = 0.002), and those who carried the T allele (41.8%, OR1.976, p = 0.002). LPS-induced TLR-4 activation of monocytes resulted in higher tumour necrosis factor-α production in patients with the IL28B CC genotype compared to non-CC individuals (p<0.01). Similarly, increased tumour necrosis factor-α, interleukin-2 and interferon-γ production by lymphocytes was found in the IL28B CC carriers (p<0.01) CONCLUSIONS: The IL28B CC genotype exerts protective effect against chronic hepatitis C-virus infection and may be a pretreatment predictor of sustained virological response during interferon-based antiviral therapy. The IL28B CC polymorphism is associated with increased Th1 cytokine production of activated peripheral blood monocytes and lymphocytes, which may play a role in interferon-induced rapid immune control and sustained virological response of pegylated interferon plus ribavirin treated patients.