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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.

This review summarizes our current knowledge of the innate and adaptive immune responses induced by hepatitis C virus, and of the genetic polymorphisms that may determine the outcome of the disease. In addition, the authors discuss the role of reactive oxygen species and oxidative stress in hepatitis C virus-related pathogenic processess, such as hepatitis, fibrosis, hepatocellular carcinoma, steatosis and insulin resistance.

Fetuin-A (also known as α2-Heremans-Schmid glycoprotein) is a multifunctional molecule secreted by the liver. It is a negative acute phase reactant with a debated role in subclinical inflammation. Fetuin-A is an inhibitor of the insulin receptor and its serum level correlates with insulin resistance. The protein has been implicated in adipocyte dysfunction and it is associated with obesity and non-alcoholic fatty liver disease. Although all these properties seem to promote atherosclerosis, the role of fetuin-A in cardiovascular diseases is more complex. As a natural inhibitor of tissue and vascular calcification, fetuin-A also acts as a protective factor in atherosclerosis. The potential role and prognostic value of fetuin-A in arterial calcification and cardiovascular diseases is discussed in this review, along with explanations for seemingly contradicting results in the literature and possible directions for future research.

Introduction: Transmethylation modifies configuration and proceeds via formaldehyde. It has a significant role for example in epigenetic regulation. The whole methyl-pool can be evaluated by the measurement of bound formaldehyde., Aim: The bound formaldehyde was measured in wheat, bean, beetroot, cabbage, broiler- and rabbit liver. The relationship between transmethylation and redox homeosthasis was studied in the liver of domestic animals, and in the rat model of fatty liver., Method: The diet of rats was enriched with cholesterol, sunflower oil and cholic acid. The bound formaldehyde was determined by overpressured layer chromatography. The hydrogen-donating ability was measured with 1.1-diphenyl-2-picrylhydrazylt free radical using spectrophotometric measurement., Results: Beans had the most bound formaldehyde. The liver of broilers possessed significantly elevated hydrogen-donating ability and transmethylation ability. Rats with severe fatty liver had significantly less bound formaldehyde and the hydrogen-donating ability tendentiously decreased., Conclusions: These results draw attention to the diet, especially in obesity and obesity-related diseases.

Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, the hepatic manifestations of metabolic syndrome with close association with inzulin resistance and obesity, are the most common liver diseases, affecting up to a third of the population worldwide. They confer increased risk for hepatocellular carcinoma as well as cardiovascular diseases. The review aims to summarize advances in epidemiology, pathogenesis and clinical management of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Besides liver biopsy and biomarkers, a novel non-invasive diagnostic tool the called "controlled attenuation parameter" measuring the attenuation of ultrasound generated by the transient elastography transducer, can quantitatively assess the hepatic fat content and differentiate between steatosis grades. At the same time, liver stiffness (fibrosis) can also be evaluated. The authors present their own results obtained with the latter procedure. In non-alcoholic fatty liver disease, the lifestyle intervention, weight loss, diet and exercise supported by cognitive behavioural therapy represent the basis of management. Components of metabolic syndrome (obesity, dyslipidaemia, diabetes and arterial hypertension) have to be treated. Although there is no approved pharmacological therapy for NASH, it seems that long lasting administration of vitamin E in association with high dose ursodeoxycholic acid may be beneficial. In addition, omega-3 polyunsaturated fatty acid substitution can also decrease liver fat, however, the optimal dose is not known yet. Further controlled clinical studies are warranted to establish the real value of any suggested treatment modalities for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, although these are in experimental phase yet.

Hepatitis C virus infection is a common liver disease worldwide, leading to the development of steatosis, cirrhosis and hepatocellular carcinoma. In patients with chronic hepatitis C virus infection the prevalence of steatosis has been estimated to be about 55%. Development of steatosis is due to both viral and metabolic factors. Hepatitis C virus proteins moderate a number of intracellular pathways, however, further studies are required to understand these mechanisms. Obesity and insulin resistance may allow the virus to resist antiviral treatment. This review discusses the relationship among steatosis, insulin resistance and the response to antiviral therapy.

Unlabelled: Changes of redox-homeostasis generate cytokines, and free radicals influence many intracellular signaling pathways in different liver diseases. Liophylised table beet and carrot powder (GPS Powder Kft. 1361/004/2003BFÁÉÉÁ) containing bioactive components such as betaine, betanins, betaxanthins, flavonoids, polyphenols, glutamine, beta carotene, vitamins and folic acid may induce changes in various cellular pathways., Aim: The aim of this study was to determine the protecting effects of bioactive agents of the liophylised table beet and carrot powder on fatty liver in a "short term" experiment., Method: Male Wistar rats were fed with chow with or without high fat (2% cholesterol, 0.5% cholic acid, 20% sunflower oil) and treated with 0.1 or 1 g/bwkg/day natural product for ten days parallel with the feedings. Cyclooxygenase-2, inducible nitric oxide synthase and tumor necrosis factor-α mRNA levels were determined using molecular biologic methods. Free radicals, H-donating activity, reducing power and free SH-group concentrations were determined by luminometry and spectrophotometry. Mobilized methyl groups were assayed by high pressure liquid chromatography method in liver homogenates., Results: It was found that the higher dose of the natural product better decreased the induced free radical reactions, cyclooxygenase-2, inducible nitric oxide synthase and tumor necrosis factor-α mRNA-levels both in normal and fatty liver tissues. Although treatments failed to exert significant changes in all global antioxidant parameters, mobilized methyl group concentrations were higher after treatments in fatty liver. Favorable tendencies were also noted in the redox-homeostasis of the fatty liver after treatment., Conclusions: As expected, lyophylised table beet and carrot proved to be a "functional food" in rats with alimentary fat induced fatty liver. It cannot be ruled out that this beneficial effect may have clinical relevance.

Subsequent studies have implicated the hepatitis C virus (HCV) core protein in the pathogenesis of hepatic steatosis. Chronic HCV infection may also cause steatosis by impairing fatty acid oxidation. There is relationship between accumulation of fat into the liver and overweight and/or obesity. Another unexpected virus-host interaction is the HCV infection and diabetes. HCV encoded proteins might alter insulin signaling thus explaining impaired insulin sensitivity and the occurrence of glycaemic dysregulation. Some pieces of the puzzle are still not well known; e.g. the factors and the spectrum of disorders associated with insulin resistance, and whether the liver is a trigger or target of metabolic syndrome? In this review article clinical consequence of chronic HCV infection, diabetes mellitus and hepatic steatosis are discussed, as well as their possible effects on antiviral therapy.

Regulatory role of the brain in energy expenditure, appetite, glucose metabolism, and central effects of insulin has been prominently studied. Certain neurons in the hypothalamus increase or decrease appetite via orexigenes and anorexigenes, regulating energy balance and food intake. Hypothalamus is the site of afferent and efferent stimuli between special nuclei and beta- and alpha cells, and it regulates induction/inhibition of glucose output from the liver. Incretines, produced in intestine and in certain brain cells (brain-gut hormones), link to special receptors in the hypothalamus. Central role of insulin has been proved both in animals and in humans. Insulin gets across the blood-brain barrier, links to special hypothalamic receptors, regulating peripheral glucose metabolism. Central glucose sensing, via "glucose-excited" and "glucose-inhibited" cells have outstanding role. Former are active in hyperglycaemia, latter in hypoglycaemia, via influencing beta- and alpha cells, independently of traditional metabolic pathways. Evidence of brain insulin resistance needs centrally acting drugs, paradigm changes in therapy and prevention of metabolic syndrome, diabetes, cardiovascular and oncological diseases.

Non-alcoholic steatosis/steatohepatitis is the most common etiology of abnormal liver function tests. Authors review the etiology, pathomechanism and clinical signs. Possibilities of the diagnosis are also summarized. There is an increasing need to find non-invasive biomarkers (TNF-α, adiponektin, end product of lipid peroxidation, cytokeratin-18, hyaluronic acid), score systems (Fibrotest, APRI), methods (Fibroscan), which would detect the progression of the disease, the development of inflammation and fibrosis. There is no proven specific therapy; the aim is the elimination of provoking factors (weight loss), treatment of diabetes mellitus and hyperlipidemia. Besides, liver protection (antioxidants) is important, as well.

Non-alcoholic fatty liver disease (NAFLD) can be found in approximately 30% of adults in industrialized societies. Non-alcoholic steatohepatitis (NASH) is its most severe histological form and progresses to cirrhosis in 20% of these patients. Once developed, 30% to 40% of patients with cirrhosis will suffer liver-related death. NAFLD is considered the hepatic manifestation of the metabolic syndrome. Recent findings linking the components of metabolic syndrome with NAFLD and the progression to nonalcoholic steatohepatitis will be reviewed; in particular, the role of visceral adipose tissue, insulin resistance, adipocytokines, oxidative stress and diminished antioxidants within the liver in the exacerbation of these conditions. It is now widely accepted that non-hepatic mechanisms are largely responsible for the development of insulin resistance, which causes hepatic steatosis. Insulin resistance, a key feature of metabolic syndrome, is crucial for NASH development. We have a classical chicken-egg problem: insulin resistance causes hepatic steatosis or vice-versa? A possible sequence of the pathogenetic events is the following: increased free fatty acid supply - increased de novo lipogenesis - triglyceride and VLDL overproduction - atherogenic dyslipidemia- oxidative stress (lipid oxidation and peroxidation) - exhaustion of antioxidant defense system- "Tsunami" of inflammatory cytokines- fibrosis- carcinogenesis. Given the strong association of NAFLD with metabolic syndrome, early recognition, assessment and management are essential. The management emphasizes weight reduction and attention to global cardiometabolic risk factors, similar to recommendations for management of the elements of metabolic syndrome.

In the past few years there has been growing interest for a type of short RNAs called microRNAs, which are involved in the regulation of gene expression mainly in a negative way. There are about 1000 known microRNA today. It has been demonstrated that expression level of microRNA may become altered from normal to diseased state, thus microRNAs could be employed as a reliable tool in the diagnosis of diseases. A liver-characteristic microRNA (miR-122) needed for functioning hepatocytes has been identified, which usually shows a decreased expression level upon liver injury. miR-122 has been suggested as a biomarker since it was downregulated in the liver tissue upon acetaminophen-induced toxicity and in turn elevated miR-122 level was detected in the plasma. Moreover, miR-122 level in the plasma was found to be more sensitive as compared with conventional assays based on the release of liver enzymes. Also, miR-122 expression tends to decrease as carcinogenesis progresses. In addition, miR-122 enhances the replication of hepatitis C virus and its level seems to influence the efficiency of interferon therapy. Nowadays, many microRNAs are known whose distinctive alterations in their specific patterns seem to characterize individual pathological processes. In this article, the major alterations in microRNA expression patterns in liver diseases such as drug- and alcohol-induced liver diseases, non-alcoholic fatty liver diseases, fibrosis, viral infections (hepatitis), cirrhosis and hepatocellular carcinoma are summarized.

Epidemiological studies in humans have documented an association between visceral obesity and cardiovascular risk factors such as dyslipidemia, insulin resistance, and type 2 diabetes mellitus. Recently, attention has been focused on the excessive accumulation of triglycerides in the liver as part of metabolic syndrome. It appears that fat accumulation in the liver is associated with several features of insulin resistance even in normal-weight and moderately overweight people.

Obesity-triggered co-morbidities, such as insulin resistance and the accompanying nonalcoholic fatty liver disease represent major health care burdens worldwide. The first step in the pathogenesis of the disease is the triglyceride deposition in the liver. The resulting hepatic steatosis may lead to steatohepatitis, cryptogenic cirrhosis and eventually, hepatocellular cancer. Steatosis develops when fatty acid uptake and lipogenesis overwhelm fatty acid oxidation and secretion. We highlight these molecular mechanisms in this review to provide further information to understand the background of nonalcoholic fatty liver disease and the cardiometabolic complications that escort obesity and insulin resistance.

The most frequent liver disorder in metabolic syndrome is the nonalcoholic fatty liver disease. Its pathogenesis is a complex, multifactorial process, characterized by insulin resistance and involvement of the endocrine system. Hypothyroidism may lead to nonalcoholic steatohepatitis via hyperlipidemia and obesity. Adult patients with growth hormone deficiency have a metabolic syndrome-like phenotype with obesity and many characteristic metabolic alterations. The chronic activation of the hypothalamic-pituitary-adrenal axis results in metabolic syndrome as well. Cushing's syndrome has also features of metabolic syndrome. Mild elevation of transaminase activities is commonly seen in patients with adrenal failure. Non-alcoholic steatosis is twice as common in postmenopusal as in premenopausal women and hormonal replacement therapy decreases the risk of steatosis. Insulin resistance, diabetes mellitus type 2, sleeping apnoe syndrome, cardiovascular disorders and non-alcoholic fatty liver disease are more frequent in polycystic ovary syndrome. Hypoandrogenism in males and hyperandrogenism in females may lead to fatty liver via obesity and insulin resistance. Adipokines (leptin, acylation stimulating protein, adiponectin) have a potential role in the pathogenesis of nonalcoholic fatty liver. The alterations of endocrine system must be considered in the background of cryptogenic liver diseases. The endocrine perspective may help the therapeutic approaches in the future.

Unlabelled: Overweight/obesity is an independent negative predictive factor of steatosis in chronic hepatitis C virus infection. The nonresponse to combined peginterferon and ribavirin treatment in infection caused by genotype 1 is associated with the waist circumference, body mass index (BMI), diabetes, steatosis, and degree of fibrosis. The obesity is an independent negative predictive factor of inefficacy of antiviral treatment., Case Report: The authors summarize the case of a 59-year-old obese (BMI = 46.47 kg/m 2 ) male patient with chronic HCV infection. The weight reduction--after two ineffective antiviral treatments--helped the biochemical and virological response to combined peginterferon-alpha-2a and ribavirin treatment. Between the combined peginterferon and ribavirin therapy, the patient was treated with amantadine and silymarin., Discussion: The authors summarize the importance of steatosis and insulin resistance in chronic HCV hepatitis as well as review the impact of weight reduction and the improvement of insulin sensitivity., Conclusion: Body-weight reduction and hepatoprotective drugs might have increased the effectiveness of combined peginterferon and ribavirin treatment and thus the sustained virological response.

Non-alcoholic fatty liver disease is present in 15-25% of the general population. The fundamental derangement in non-alcoholic fatty liver disease is insulin resistance, a key component of the metabolic syndrome, which includes type 2 diabetes mellitus, dyslipidemia, hypertension, and obesity. The natural history of non-alcoholic fatty liver disease is not always benign, and causality for chronic liver disease and cirrhosis is well known in clinical practice and sometimes it is accompanied by hepatocellular carcinoma. Non-alcoholic fatty liver disease is likely to be associated with increased cardiovascular disease risk, and it raises the possibility that non-alcoholic fatty liver disease may be not only a marker but also an early mediator of atherosclerosis. Therapy is currently directed at treating components of the metabolic syndrome which may be beneficial also for the liver.

The abnormal lipid accumulation in the parenchymal cells of the liver is called fatty liver. In the background of this disease is the imbalance of fat accumulation and fat consumption: the overproduction of triglycerides is accumulated in the hepatocytes. Normally 5% of the cells contain triglycerides, but this value can increase to over 50% in fatty liver. It is called fatty infiltration under 50%, and fatty liver over 50%. This alteration does not cause cell function disturbance in mild forms, but it does in severe forms. In many cases it is the first sign of cell necrosis. Fatty liver must be taken seriously as it makes the liver sensitive to other toxic effects. It is not an independent disease, in many cases it is part of some other pathologic process. In the first phase (before the development of fibrosis) it is reversible, when the inducing cause disappears, the liver metabolizes the excessive triglycerides. In the treatment the basic process should be treated. So far no specific drug is known that would be able to decrease the fat accumulated in the hepatocytes.

Introduction: Non-Alcoholic Fatty Liver Disease is an acquired metabolic disease of the liver caused by accumulation of triglycerides in hepatocytes that is followed by necrobiotic inflammatory reaction, fibrosis and cirrhosis. Obesity, insulin resistance, diabetes mellitus and hyperlipidaemia are important pathogenetic factors of the process. It is known that among patients with cholecystolithiasis and diabetes mellitus in their anamnesis complications of cholecystolithiasis occur much more frequently like among patients without diabetes., Aim: The aim of the study is observation of the incidence of cholecystolithiasis and its complications in patients with Non-Alcoholic Fatty Liver Disease and comparison of cholecystolithiasis incidence between healthy population and population with Non-Alcoholic Fatty Liver Disease., Methods: Abdominal ultrasonographical findings were analysed in patients hospitalised at our department and in outpatients, patients with severe accompanied diseases were excluded of the analysis. The analysed basic file of patients could be considered as a selected file. The independence of the two examined variables was measured by chi(2) test., Results: Steatosis was described in 38% of the examined patients, cholecystolithiasis was described in 16% of patients. Cholecystolithiasis and its complications occur two times more frequently in patients with Non-Alcoholic Fatty Liver Disease (33%) like Non-Alcoholic Fatty Liver Disease in patients with cholecystolithiasis (16%). Complications of cholecystolithiasis occur more frequently among patients with Non-Alcoholic Fatty Liver Disease like in healthy individuals. The chi(2) test did not bring significant results concerning the independence of cholecystolithiasis and Non-Alcoholic Fatty Liver Disease., Conclusion: Pathogenetic factors of Non-Alcoholic Fatty Liver Disease participate in the pathogenesis of cholecystolithiasis. Their common pathogenetic factors bring about that the formation of cholecystolithiasis is probably faster than the progression of steatosis.

The metabolic syndrome is one of the most common disease of our era that may cause numerous complications. There are some studies showing the need to take attention to the hepatic manifestation of the metabolic syndrome besides its already well-known consequences. In most of the cases there are histopathological evidences for the presence of fatty liver and mainly non alcoholic steatohepatitis. These conditions can lead to hepatic cirrhosis, hepatic failure or even to hepatocellular carcinoma. The risk of these consequences is the greater the more severe the metabolic syndrome is and the more components of it are included. All these emphasise the importance of examining the hepathological status of the patients suffering from the metabolic syndrome.

The liver steatosis is a frequent human disease. The most frequent cause of the process is the alcohol consumption. But it also may arise without significant alcohol abuse. This pathogenetic process is called non-alcoholic steatohepatitis (NASH), that is characterized by the same conditions like the alcoholic steatohepatitis. In the pathogenesis of the NASH various factors participate i.e. obesity, diabetes mellitus type II, hyperlipidaemia, pregnancy, variable chemotoxins, parenteral nutrition, jejunoileal bypass, chronic inflammatory diseases, protein deficient nutrition and inborn metabolic diseases. Pathobiochemically the process consists of oxidative stress and lipid peroxidation. This condition comes from the progressive accumulation of the free fatty acids in mitochondria and from the induction of cytochrome P450, CYP 2E1 isoform in hepatocytes and Kupffer cells. The free fatty acids and ketons can cause the induction of CYP 2E1 system, that is why diabetes mellitus and obesity are the two most important factors in the NASH pathogenesis. This article is concerned mainly in the explanation of NASH pathomechanism.

CCl4 is an organic solvent and a well known hepatotoxic agent. Injury is mediated by reactive free radicals, mainly-CCl3 (trichloromethyl). Liver lesion develops within one-two hours, however, late toxic effects may appear after a delay of several hours or two to three days. Some drugs and liver toxicants cause disturbances in synthesis and metabolism of triglycerides, cholesterol and lipoproteins, thus damaging the basic resource for living cells. In our experiments a single 1.25 ml/kg CCl4 dose was administered s.c. to male Wistar rats. 24 hours later triglyceride level increased in the plasma by 223%. Cholesterol content suffered no changes. HDL-C level decreased by 40%. LDL-C concentration was higher by 235%. Cholesterol/HDL-C ratio increased by 0.75% on account of the practically unchanged cholesterol amount in the blood. The most often used calculation (Friedewald equation) LDL-C/HDL-C ratio was higher by 305%. The increased triglyceride content in the blood is in correlation with the fatty degeneration of the liver. The high LDL-C/HDL-C ratio may point to incipient atherosclerotic complications. The pathological lipid levels measured 24 hours after intoxication claim for delayed toxic effects to be taken into consideration. It may be suggested to determine the main lipid parameters after carbon tetrachloride exposition.