[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.

[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.

[Gut-liver axis in inflammatory bowel disease. A retrospective study]. / A bél­máj tengely vizsgálata colitis ulcerosában. Retrospektív tanulmány.

INTRODUCTION: Examination of the gut-liver axis came into the spotlight worldwide. Liver enzyme elevations are commonly seen in patients with inflammatory bowel disease (IBD), which is a diagnostic challenge in everyday clinical practice. Liver and biliary diseases are common extra-intestinal manifestations in Crohn's disease and ulcerative colitis. The assessment of routine liver function tests could be an inaccurate reflection of liver damage, so its prevalence could be underestimated. There would be a need for non-invasive biomarkers and/or scoring systems, which would help the diagnosis of liver damage associated with intestinal diseases. AIM: In our work we considered to highlight the importance of the gut-liver axis significance. We used data of patients suffering from ulcerative colitis, as a model for bowel diseases to understand the underlying factors of the pathogenesis of hepatobiliary manifestations. METHOD: In our retrospective study, we investigated the data of 100 ulcerative colitis patients (male = 46, female = 54) (mean age: 42.5 ± 12.7) and compared to healthy controls (n = 42) (male = 17, female = 25) (mean age: 40.2 ± 13.5). Liver function tests (ALT, AST, GGT, ALP, bilirubin, albumin, thrombocyte), bile acid levels were determinated, and various free radical markers (global, enzymatic) were used to assess the redox homeostasis of patients. Hydrogen donor activity, reducing power, superoxide dismutase and glutathione peroxidase activity, total antioxidant status and induced chemiluminescence were measured, considering that the patients received 5-aminosalicilate and/or azathioprin and elemental diet treatment. RESULTS: Liver function parameters were increased in ulcerative colitis patients, and total antioxidant status, as well. Reducing power significantly decreased, but there was no significant difference compared to the control group of glutathione peroxidase and H-donor activity, we observed only tendentious decrease. The antioxidant protection of more than 54% of patients had a significantly lower rate, according to all the parameters. With chemiluminescence measurement we measured better free radical scavenging capacity, both in plasma and in erythrocytes as a result of the therapy, however, it showed an increase of superoxide dismutase activity, which warns of inflammatory processes. The cause of the decrease in bile acid levels found in the group of ulcerative colitis patients, can be the accelerated peristaltic. CONCLUSIONS: In the daily routine, liver enzyme values do not give an accurate picture of liver damage associated with ulcerative colitis. With the help of various specific parameters determined by us, we can estimate the background processes of the gut-liver axis alterations. The decrease in bile acid levels can be a predictive factor in ulcerative colitis. Our work highlights the need of non-invasive screening for liver diseases in inflammatory bowel disease. Orv Hetil. 2017; 158(26): 1014-1021.

[Various pathways leading to the progression of chronic liver diseases]. / Az idült májbetegségek progressziójához vezeto folyamatok.

As the result of various effects (viruses, metabolic diseases, nutritional factors, toxic agents, autoimmune processes) abnormal liver function, liver steatosis and connective tissue remodeling may develop. Progression of this process is complex including various pathways and a number of factors. The authors summarize the factors involved in the progression of chronic liver disease. They describe the role of cells and the produced inflammatory mediators and cytokines, as well as the relationship between the disease and the intestinal flora. They emphasize the role of oxidative stress, mitochondrial dysfunction and cell death in disease progression. Insulin resistance and micro-elements (iron, copper) in relation to liver damage are also discussed, and genetic and epigenetic aspects underlying disease progression are summarized. Discovery of novel treatment options, assessment of the effectiveness of treatment, as well as the success and proper timing of liver transplantation may depend on a better understanding of the process of disease progression.

[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.

[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.

[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.

[The significance of omega-3 fatty acids in the treatment of non-alcoholic fatty liver disease]. / Az ómega-3 zsírsavak jelentosége a nem alkoholos zsírmájbetegség kezelésében.

Today, non-alcoholic fatty liver disease is the most common chronic liver disease, yet there is no clearly accepted effective therapy. What is certain is that the number of people suffering from the disease is increasing, making prevention, treatment and recognition of co-morbidities of paramount importance. Current evidence suggests that the development of non-alcoholic fatty liver disease may be due to pathological factors of different origins. The main risk factors include genetic factors, acquired environmental influences and lifestyle. Lifestyle modification, i.e., the elimination or reduction of these harmful factors, can reverse liver damage, depending on the stage of the disease. In this summary statement, we review the pathophysiology of non-alcoholic fatty liver disease, risk factors and therapeutic options, within that in particular lifestyle modification (dietary changes, increasing physical activity, weight loss). Furthermore, we also show the importance of omega-3 fatty acids such as eicosapentaenoic acid and docosahexaenoic acid in detail. With our knowledge, the personalized treatment of non-alcoholic fatty liver disease can be elaborated. Orv Hetil. 2023; 164(33): 1294-1299.

Metronidazole does not show direct antioxidant activity in in vitro global systems.

Metronidazole has been widely used topically and systemically for more than 50 years but data on its antioxidant properties are still incomplete, unclear and contradictory. Its antioxidant properties are primarily hypothesized based on in vivo results, therefore, studies have been performed to determine whether metronidazole has antioxidant activity in vitro. We used so-called global spectrophotometric and luminometric methods. Fe3+/Fe2+-reducing ability, hydrogen donor activity, hydroxyl radical scavenging property and lipid peroxidation inhibitory activity were investigated. Under the condition used, metronidazole has negligible iron-reducing ability and hydrogen donor activity. The hydroxyl radical scavenging capacity cannot be demonstrated. It acts as a pro-oxidant in the H2O2/.OH-microperoxidase-luminol system, but it can inhibit the induced lipid peroxidation. According to our results, metronidazole has not shown antioxidant activity in vitro but can affect redox homeostasis by a ROS-independent mechanism due to its non-direct antioxidant properties.

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.

Impact of milk thistle (Silybum marianum) on the mycotoxin caused redox-homeostasis imbalance of ducks liver.

The Fusarium mycotoxins deoxynivalenol (DON) and zearalenone (ZEA) frequently contaminate grain crops, especially maize, the basis of poultry's feed. Mycotoxins enter the food chain and induce pathological changes in edible tissues. Milk thistle (Silybum marianum) has been used for the treatment of liver disease in humans because of its antioxidant and hepatoprotective effects, but its utility in veterinary use is poorly examined. To investigate possible protective properties against mycotoxin caused oxidative stress in poultry, pressed form of milk thistle seed (0.5%) was tested in white, female, Hungarian ducks over a feeding period of 47 days. Ducks were separated into 3 groups. The first group was fed with normal diet. The second group was fed with normal diet contaminated with DON (4.9 mg/kg) and ZEA (0.66 mg/kg). The third group received mycotoxin contaminated feed with milk thistle supplementation. Histological examination, markers of the redox status and metal element concentration measurements were carried out. The results showed alterations in the histological examination and in the redox homeostasis markers as a short-term effect by strengthening the antioxidant system. Acute exposure of mycotoxins caused an oxidative stress, which induced an effective antioxidant defensive response of the organism indicated by the free sulfhydryl group content (from 0.72 ± 0.06 to 0.77 ± 0.11) and the reducing power (0.49 ± 0.06 to 0.52 ± 0.08) elevation. The short-term free radical injury may be compensated by the liver resulting in decreased lipid peroxidation markers (malondialdehyde concentration: from 16.86 ± 0.49 to 0.94 ± 0.15, conjugated diene concentration: from 0.21 ± 0.07 to 0.17 ± 0.03). Silymarin further strengthtened the antioxidant defense by the elevation of sulfhydryl groups concentration and reducing power property resulted in decreased total scavenger capacity. However the concentration of lipid peroxidation markers were further elevated by the used antioxidant treatment (MDA: 5.2 ± 0.35, DC: 0.26 ± 0.08). In conclusion, the mycotoxin-contamination activated effectively the antioxidant system. The milk thistle supplementation has cytoprotective effects according to the histological findings, activated the antioxidant system, however the elevation of lipid peroxidation products need further explanation.

Changes in endogenous metal element concentrations in various aetiologies of chronic liver disease. / Az endogén fémionok koncentrációinak változása különbözo kórokú, idült májbetegségekben.

Our body contains physiologically many metal ions used for its metabolic processes and function. Metal ion changes can start pathological processes, however, the pathological processes may also lead to changes in metal ion concentration. In this study, the authors summarize the physiologically present metal ions' change in liver diseases with various aetiologies, the consequences are discussed as well as the connections with the progression. Further, the authors point out the element concentration changes as diagnostic or prognostic values for the liver diseases as well. Orv Hetil. 2020; 161(22): 917-923.

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.

Metal- and redox homeostasis in prostate cancer with vitamin D3 supplementation.

Vitamin D3 supplementation has a beneficial effect on cancerous patients, although it can influence the redox- and metal homeostasis. The aim of our investigation was to demonstrate the effect of vitamin D3 consumption on the redox- and metal homeostasis in prostate cancer, because of the recommended daily dose increased from 200 IU to 2000 IU in recent years in Hungary. Forty-three volunteers were involved in the study. The grouping was applied according to the clinical routine laboratory parameters (vitamin D3) and the tumor markers (PSA, fPFA). Patients were divided into 5 groups: (A) patient control (N = 8), (B) patient control with vitamin D3 treatment (N = 9), (C) high-risk prostate cancer group (N = 6), (D) high-risk prostate cancer group with vitamin D3 treatment (N = 8) and (E) vitamin D3 treated cancerous group with androgen deprivation therapy (N = 11). The element concentrations were determined with ICP-OES. Among the redox parameters, free radical scavenging capacity and H-donating ability were determined with luminometry and spectrometry. Vitamin D3 treatment caused differences in the metal- and redox homeostasis in either patient control and cancerous groups. The concentration of Fe, Cr, and Pb significantly increased in the erythrocytes of prostate cancer patients. According to the higher scavenging capacity by vitamin D3 treatment, it seems that vitamin D3 helps to equilibrate the redox homeostasis that could affect the outcome of cancer positively. However, the tendency in the metal element status does not give a clear explanation of cancer's outcome, but the accumulation of Pb by vitamin D3 supplementation needs to be taken into more serious consideration in set terms of occupational diseases.