ArticleLiterature Review

Silymarin and S-adenosyl-L-methionine (SAMe): Two promising pharmacological agents in case of chronic alcoholic hepathopathy. A review and a point of view

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Abstract

The alcoholic liver disease (ALD) is the leading cause of death from liver failure in Italy and worldwide. Ethanol abstention, a healthy diet, and a significant improvement of life-style are the mainstay of treatment for this disease. Currently, we do not have effective therapeutic options are at our disposal to restore and maintain an improved clinical status. Silymarin is a complementary and alternative medicine often prescribed and self-prescribed; it has anti-oxidant, anti-inflammatory, anti-fibrotic, and metabolic properties. It improves the laboratoristic values and the ultrasonographic grading of liver disease in case of steatosis/steatohepatitis. S-adenosyl-L-methionine (SAMe) is the principal biological methyl donor, and it is also a precursor of glutathione (GSH), essential for the anti-oxidant pathways. SAMe is particularly important for opposing the toxicity of free radicals generated by various toxins, including alcohol. An association between Silymarin and SAMe (labelled as a dietary supplement) has been recently brought to market, and seems to be promising. It could be beneficial in such cases of alcoholic hepathopathies. New therapeutic options are needed by hepatologists to successfully overcome a constantly growing disease.

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... In particular, SM has been the gold standard drug to treat liver disorders of different etiologies and milk thistle extracts have been used as traditional herbal remedies ("liver tonics") for almost 2000 years. Therefore, SM is most well known for its antioxidant and chemoprotective effects on the liver [5][6][7][8][9][10][11] and it is often prescribed and self-prescribed as a complementary and alternative hepatoprotective medicine [12]. SM is being studied as a hepato-, neuro-, nephro-and cardio-protective ingredient due to its strong antioxidant and tissue regenerative properties [12][13][14][15][16][17]. ...
... Therefore, SM is most well known for its antioxidant and chemoprotective effects on the liver [5][6][7][8][9][10][11] and it is often prescribed and self-prescribed as a complementary and alternative hepatoprotective medicine [12]. SM is being studied as a hepato-, neuro-, nephro-and cardio-protective ingredient due to its strong antioxidant and tissue regenerative properties [12][13][14][15][16][17]. There is a range of recent comprehensive reviews covering various routes and mechanisms of action of SM in animal models and human trials [13][14][15][16][17] very often referring to its antioxidant properties. ...
Article
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Silymarin (SM), an extract from the Silybum marianum (milk thistle) plant containing various flavonolignans (with silybin being the major one), has received a tremendous amount of attention over the last decade as a herbal remedy for liver treatment. In many cases, the antioxidant properties of SM are considered to be responsible for its protective actions. Possible antioxidant mechanisms of SM are evaluated in this review. (1) Direct scavenging free radicals and chelating free Fe and Cu are mainly effective in the gut. (2) Preventing free radical formation by inhibiting specific ROS-producing enzymes, or improving an integrity of mitochondria in stress conditions, are of great importance. (3) Maintaining an optimal redox balance in the cell by activating a range of antioxidant enzymes and non-enzymatic antioxidants, mainly via Nrf2 activation is probably the main driving force of antioxidant (AO) action of SM. (4) Decreasing inflammatory responses by inhibiting NF-κB pathways is an emerging mechanism of SM protective effects in liver toxicity and various liver diseases. (5) Activating vitagenes, responsible for synthesis of protective molecules, including heat shock proteins (HSPs), thioredoxin and sirtuins and providing additional protection in stress conditions deserves more attention. (6) Affecting the microenvironment of the gut, including SM-bacteria interactions, awaits future investigations. (7) In animal nutrition and disease prevention strategy, SM alone, or in OPEN ACCESS Antioxidants 2015, 4 205 combination with other hepatho-active compounds (carnitine, betaine, vitamin B12, etc.), might have similar hepatoprotective effects as described in human nutrition.
... Although NAC has been suggested as the best candidate, NACbased antioxidant therapies could not improve severe forms of alcoholic hepatitis in randomized studies 45,46 . Other natural products, such as resveratrol 47 , silymarin 48 , and green tea-derived EGCG 49 , were characterized as effective hepato-protective agents against ALD. However, their targeted 'immediate molecules' on the cell membrane and therapeutic efficacy in ALD patients were not well studied. ...
Article
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Alcoholic liver disease (ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S-allylmercaptocysteine (SAMC) from aged garlic on liver cell injury. A chronic ethanol-fed ALD in vivo model (the NIAAA model) was used to test the protective functions of SAMC. It was observed that SAMC (300 mg/kg, by gavage method) effectively ameliorated ALD-induced body weight reduction, steatosis, insulin resistance, and inflammation without affecting the health status of the control mice, as demonstrated by histological, biochemical, and molecular biology assays. By using biophysical assays and molecular docking, we demonstrated that SAMC directly targeted insulin receptor (INSR) protein on the cell membrane and then restored downstream IRS-1/AKT/GSK3β signaling. Liver-specific knock-down in mice and siRNA-mediated knock-down in AML-12 cells of Insr significantly impaired SAMC (250 μmol/L in cells)-mediated protection. Restoration of the IRS-1/AKT signaling partly recovered hepatic injury and further contributed to SAMC's beneficial effects. Continuous administration of AKT agonist and recombinant IGF-1 in combination with SAMC showed hepato-protection in the mice model. Long-term (90-day) administration of SAMC had no obvious adverse effect on healthy mice. We conclude that SAMC is an effective and safe hepato-protective complimentary agent against ALD partly through the direct binding of INSR and partial regulation of the IRS-1/AKT/GSK3β pathway.
... Post-White et al., 2007;Trappoliere et al., 2009; Loguercio et al., 2011; Loguercio et al., 2012) and it is frequently prescribed and self-prescribed as an additional and alternative hepatoprotective drug(Testino et al., 2013). Since it is efficient in restoration of liver function and regeneration of liver cells, silymarin has been widely used to remedy various liver disorders(Pradhan et al., 2006; Dixit el al., 2007; Govind et al., 2008; Tůmova et al. 2010), such as alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, drug-induced liver injury and mushroom poisoning(Abenavoli et al., 2018), steatohepatitis(Milosevic et al., 2014), and cirrhosis(Parés et al., 1998). ...
Article
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This review provides a systematic and in-depth overview of the promise and potential of milk thistle (Silybum marianum) as an interesting alternative nutraceutical preparation for pharmaceutical and medicinal applications. Moreover, it aims to summarize and update the existing evidence of extract of milk thistle in the treatment of various diseases by in vitro, in vivo, and clinical studies, and special care is paid to the action mechanisms. The main active component of milk thistle, collectively known as silymarin, consists of a mixture of flavonolignans and flavonoid taxifolin. Silymarin acts as a hepatoprotective, anticancer, anti-inflammatory, immunomodulatory, neuroprotective and lactogenic agent. Precise mechanisms of silymarin action still needs investigations and molecular/genetic background of silymarin synthesis is crucial to be elucidated for reinforcement of the therapeutical potential of the plant by breeding.
... Silymarín je známy najmä vďaka svojim regeneračným a chemoprotektívnym účinkom na pečeň, vďaka čomu je často vyhľadávaným a používaným hepatoprotektívnym agensom (Testino et al., 2013). Vzhľadom na jeho schopnosť regenerovať pečeňové bunky sa používa pri liečbe rôznych ochorení tohto detoxikačného orgánu, ako je alkoholové poškodenie pečene, nealkoholové tukové ochorenie pečene, vírusová hepatitída, poškodenie pečene v dôsledku intoxikácie xenobiotikami a hubami, steatohepatitída a cirhóza pečene (Abenavoli et al., 2018). ...
... Silymarín je známy najmä vďaka svojim regeneračným a chemoprotektívnym účinkom na pečeň, vďaka čomu je často vyhľadávaným a používaným hepatoprotektívnym agensom (Testino et al., 2013). Vzhľadom na jeho schopnosť regenerovať pečeňové bunky sa používa pri liečbe rôznych ochorení tohto detoxikačného orgánu, ako je alkoholové poškodenie pečene, nealkoholové tukové ochorenie pečene, vírusová hepatitída, poškodenie pečene v dôsledku intoxikácie xenobiotikami a hubami, steatohepatitída a cirhóza pečene (Abenavoli et al., 2018). ...
Conference Paper
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V poslednom období sa čoraz viac pozornosti vedeckej komunity sústreďuje na využitie primárneho extraktu z plodov pestreca mariánskeho, t.j. silymarínu (štandardizovaná zmes flavonolignanov) pri liečbe rôznych ochorení. Predkladaný príspevok je zameraný na zosumarizovanie potenciálnych benefičných účinkov uvedeného extraktu na zdravie ľudí a zvierat, ktorý štrukturálne pozostáva zo siedmich hlavných flavonolignanov (silybín A, silybín B, izosilybín A, izosilybín B, silydianín, silychristín a izosilychristín) a flavonoidu taxifolínu. Preventívny a terapeutický účinok silymarínu bol potvrdený u ľudí a rôznych experimentálnych zvierat s ochoreniami pečene. Okrem hepatoprotektívneho účinku vykazuje silymarín tiež protirakovinové, protizápalové, neuroprotektívne, laktogénne a ďalšie farmakologické vlastnosti. Účinnosť pestreca mariánskeho v prevencii a terapii viacerých ochorení predurčuje jeho sľubné využitie v rámci alternatívnej medicíny.
... Therefore, the therapeutic activity of this compound on ALD is yet to be determined. In addition, the clinical efficacy of SAMe as a treatment for ALD should be further established in large-scale research with the help of well-designed trials [73,94]. ...
Article
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Alcoholic liver disease (ALD) refers to the damages to the liver and its functions due to alcohol overconsumption. It consists of fatty liver/steatosis, alcoholic hepatitis, steatohepatitis, chronic hepatitis with liver fibrosis or cirrhosis, and hepatocellular carcinoma. However, the mechanisms behind the pathogenesis of alcoholic liver disease are extremely complicated due to the involvement of immune cells, adipose tissues, and genetic diversity. Clinically, the diagnosis of ALD is not yet well developed. Therefore, the number of patients in advanced stages has increased due to the failure of proper early detection and treatment. At present, abstinence and nutritional therapy remain the conventional therapeutic interventions for ALD. Moreover, the therapies which target the TNF receptor superfamily, hormones, antioxidant signals, and MicroRNAs are used as treatments for ALD. In particular, mesenchymal stem cells (MSCs) are gaining attention as a potential therapeutic target of ALD. Therefore, in this review, we have summarized the current understandings of the pathogenesis and diagnosis of ALD. Moreover, we also discuss the various existing treatment strategies while focusing on promising therapeutic approaches for ALD.
... Today silymarin is best known for its antioxidant and chemoprotective effects on the liver [4], and is often either prescribed or self-prescribed as a complementary hepatoprotective medicine [5]. It has also gained attention due to its hypocholesterolemic, cardioprotective, neuroactive and neuroprotective properties [4]. ...
Article
Silymarin, the active constituent of Silybum marianum (milk thistle), and its main component, silybin, are products with well-known hepatoprotective, cytoprotective, antioxidant, and chemopreventative properties. Despite substantial in vitro and in vivo investigations of these flavonolignans, their mechanisms of action and potential toxic effects are not fully defined. In this study we explored important ADME/Tox properties and biochemical interactions of selected flavonolignans using in silico methods. A quantitative structure-activity relationship (QSAR) model based on data from a parallel artificial membrane permeability assay (PAMPA) was used to estimate bioavailability after oral administration. Toxic effects and metabolic transformations were predicted using the knowledge-based expert systems Derek Nexus and Meteor Nexus (Lhasa Ltd). Potential estrogenic activity of the studied silybin congeners was outlined. To address further the stereospecificity of this effect the stereoisomeric forms of silybin were docked into the ligand-binding domain of the human estrogen receptor alpha (ERa) (MOE software, CCG). According to our results both stereoisomers can be accommodated into the ERa active site, but different poses and interactions were observed for silybin A and silybin B.
... Silybin, as the major flavonolignan component of silymarin, is present as a quasi-equimolar mixture of the two diastereomers A and B (natural racemic silybin is noted below as silybin AB). Nowadays, silymarin is the best known for its antioxidant and chemoprotective effects on the liver (Křen and Walterová, 2005) and is often prescribed or self-prescribed as a complementary hepatoprotective medicine (Testino et al., 2013). Furthermore, its use has been broadened to other organs in addition to the liver, e.g. in the treatment of pancreatic diseases and balancing glycaemia, lung and kidney diseases, in dermatological and cosmetic preparations. ...
Article
Background: In recent years the number of natural products used as pharmaceuticals, components of dietary supplements and cosmetics has increased tremendously requiring more extensive evaluation of their pharmacokinetic properties. Purpose: This study aims at combining in vitro and in silico methods to evaluate the gastrointestinal absorption (GIA) of natural flavonolignans from milk thistle (Silybum marianum (L.) Gaertn.) and their derivatives. Methods: A parallel artificial membrane permeability assay (PAMPA) was used to evaluate the transcellular permeability of the plant main components. A dataset of 269 compounds with measured PAMPA values and specialized software tools for calculating molecular descriptors were utilized to develop a quantitative structure-activity relationship (QSAR) model to predict PAMPA permeability. Results: The PAMPA permeabilities of 7 compounds constituting the main components of the milk thistle were measured and their GIA was evaluated. A freely-available and easy to use QSAR model predicting PAMPA permeability from calculated physico-chemical molecular descriptors was derived and validated on an external dataset of 783 compounds with known GIA. The predicted permeability values correlated well with obtained in vitro results. The QSAR model was further applied to predict the GIA of 31 experimentally untested flavonolignans. Conclusions: According to both in vitro and in silico results most flavonolignans are highly permeable in the gastrointestinal tract, which is a prerequisite for sufficient bioavailability and use as lead structures in drug development. The combined in vitro/in silico approach can be used for the preliminary evaluation of GIA and to guide further laboratory experiments on pharmacokinetic characterization of bioactive compounds, including natural products.
... Preclinical and clinical studies suggest that SAMe can improve liver function (eg, decreased transaminase levels) or liver disease outcomes in hepatitis, alcoholic and viral liver cirrhosis, and cholestasis. 73,[128][129][130][131][132][133] In the largest study in this group, Mato and colleagues 131 conducted an RCT with 123 patients with alcoholic liver cirrhosis. The primary outcome, measured as the overall all-cause mortality or liver transplantation at 2-year study end point, was 30% in the placebo group and 16% in the SAMe group, although the difference was not statistically significant (P = .077). ...
Article
Objective: A systematic review on S-adenosylmethionine (SAMe) for treatment of neuropsychiatric conditions and comorbid medical conditions. Data sources: Searches were conducted in PubMed, EMBASE, PsycINFO, Cochrane Library, CINAHL, and Google Scholar databases between July 15, 2015, and September 28, 2016, by combining search terms for SAMe (s-adenosyl methionine or s-adenosyl-l-methionine) with terms for relevant disease states (major depressive disorder, MDD, depression, perinatal depression, human immunodeficiency virus, HIV, Parkinson's, Alzheimer's, dementia, anxiety, schizophrenia, psychotic, 22q11.2, substance abuse, fibromyalgia, osteoarthritis, hepatitis, or cirrhosis). Additional studies were identified from prior literature. Ongoing clinical trials were identified through clinical trial registries. Study selection: Of the 174 records retrieved, 21 were excluded, as they were not original investigations. An additional 21 records were excluded for falling outside the scope of this review. Of the 132 studies included in this review, 115 were clinical trials and 17 were preclinical studies. Data extraction: A wide range of studies was included in this review to capture information that would be of interest to psychiatrists in clinical practice. Results: This review of SAMe in the treatment of major depressive disorder found promising but limited evidence of efficacy and safety to support its use as a monotherapy and as an augmentation for other antidepressants. Additionally, preliminary evidence suggests that SAMe may ameliorate symptoms in certain neurocognitive, substance use, and psychotic disorders and comorbid medical conditions. Conclusions: S-adenosylmethionine holds promise as a treatment for multiple neuropsychiatric conditions, but the body of evidence has limitations. The encouraging findings support further study of SAMe in both psychiatric and comorbid medical illnesses.
... Future studies should also measure the degree of oxidative stress in the liver and systemically to identify those patients that would benefit from antioxidant therapies. In this regard, the combination between Silymarin and SAMe has been recently brought to market, and this combination appears to have a promising effect on patients with ALD [28]. Prospective clinical trials in patients with ALD are needed to test this therapeutic approach. ...
... S. marianum callus may serve as alternative source for liver protective pharmacological drugs and thus callus-based approaches would be of significant interest for economic and ecological reasons [26][27] . Callus induction from cotyledons in the present study was strongly affected by endogenous and exogenous factors. ...
Article
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In the present work plant tissue culture is used as a powerful technology to synthesize pharmacologically relevant secondary compounds from Silybum marianum L. This plant produces silymarin, highly effective hepato-protective compound. Tissue culture medium composition was modified to explore the possibility to increase biomass production of S. marianum callus and eventually to enhance the accumulation and yield of silymarin. In a systematic approach, levels of asparagine(Asn), 6-benzyl aminopurine (BAP), 2,4-dichlorophenoxyacetic acid (2,4-D) and myo-inositol were altered and callus growth was assessed together with levels of nitrogen metabolites especially total soluble amino acids, protein and flavolignan silymarin. Supplementation with 2,4-D dominated high callus growth characteristics. 2,4-D could partly be substituted by other growth regulators. The best medium (F) which produced the greatest callus growth consisted of 0.25 mg/l 2,4-D with 50 mg/l Asn, 0.05 mg/l BAP and 50 mg/l inositol. Additional improvement of the medium was achieved through addition of elicitors and precursors to (F media) which also enhanced the silymarin accumulation. Phenylalanine at 25 µM as precursor increased silymarin accumulation by 31% while the elicitation with glutathione at 0.1mM after 8 days and ascorbate at 0.5 mM after 8 days increased silymarin accumulation by 6.4 and 30.6 % respectively. Thus medium F in combination with 25 µM phenylalanine or 0.5 mM ascorbate in short term experiments led to optimal callus mass production with reasonable high content of silymarin.
... Glycyrrhizin also has been combined with matrine to improve CCL4-induced liver fibrosis through lowering levels of collagen and less HSC proliferation [152] , suggesting the positive effect of their combination to protect against liver fibrosis. Recently, a combination of silymarin and SAM was evaluated in ALD markets with much promise [153] . There have been some cases of adverse events and hepatotoxicity caused by herbal medicines [154] . ...
... Glycyrrhizin also has been combined with matrine to improve CCL4-induced liver fibrosis through lowering levels of collagen and less HSC proliferation [152] , suggesting the positive effect of their combination to protect against liver fibrosis. Recently, a combination of silymarin and SAM was evaluated in ALD markets with much promise [153] . There have been some cases of adverse events and hepatotoxicity caused by herbal medicines [154] . ...
Article
Alcohol consumption is one of the main risks to public health. Alcohol Use Disorders (AUDs) cause 80% of hepatotoxic deaths, and approximately 50% of cirrhosis is alcoholrelated. The acceptable daily intake (ADI) for ethanol is 2.6 g/day, deduced from morbidity and mortality rates due to liver fibrosis. The relative risk of cirrhosis increases significantly for doses above 60 g/day for men and 20 g/day for women over a period of around 10 years. Twenty to 40% of steatosis cases will evolve into steatohepatitis / steatofibrosis, and 8 to 20% will evolve directly into liver cirrhosis. About 20 to 40% of steatohepatitis cases will evolve into cirrhosis, and 4 to 5% into hepatocellular carcinoma. This cascade of events evolves in 5 to 40 years, with the temporal variability caused by the subjects' genetic patterns and associated risk / comorbidity factors. Steatohepatitis should be considered "the rate limiting step": usually, it can be resolved through abstinence, although for some patients, once this situation develops, it is not substantially modified by abstention and there is a risk of fibrotic evolution. Early detection of fibrosis, obtained by hepatic elastography, is a crucial step in patients with AUDs. Such strategy allows patients to be included in a detoxification program in order to achieve abstention. Drugs such as silybin, metadoxine, and adenosylmethionine can be used. Oher drugs, with promising antifibrotic effects, are currently under study. In this review, we discuss clinical and pathogenetic aspects of alcoholrelated liver fibrosis and present and future strategies to prevent cirrhosis.
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The present study aimed to evaluate the hepatoprotective effect and mechanism of action of Gynura procumbens on acute and chronic ethanol-induced liver injuries. Ethanol extract from Gynura procumbens stems (EEGS) attenuated acute ethanol-induced serum alanine aminotransferase levels and hepatic lipid accumulation. Therefore, EEGS was successively extracted by petroleum, ethyl acetate and n-butyl alcohol. The results showed that the n-butyl alcohol extract was the active fraction of EEGS, and hence it was further fractionated on a polyamide glass column. The 60% ethanol-eluted fraction that contained 13.6% chlorogenic acid was the most active fraction, and its effect was further evaluated using a chronic model. Both the n-butyl alcohol extract and the 60% ethanol-eluted fraction inhibited chronic ethanol-induced hepatic lipid accumulation by modulating lipid metabolism-related regulators through MAPK/SREBP-1c-dependent and -independent signaling pathways, and ameliorated liver steatosis. Our findings suggest that EEGS and one of its active ingredients, chlorogenic acid, may be developed as potential effective agents for ethanol-induced liver injury.
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It has been established that alcohol consumption is associated with elevated cancer incidence and mortality. Recently the International Agency for Cancer Research (World Health Organization) stated that acetaldehyde associated with alcoholic beverages is carcinogenic to humans and confirmed the Group 1 classification of alcohol consumption and of ethanol in alcoholic beverages. Alcohol causes cancers of the oral cavity, pharynx, larynx, oesophagus, colorectum, liver and female breast. Very little is known about safe margins of alcohol consumption. There is a dose-response relationship between alcohol and cancer risk for men and women, with studies showing that the risk of cancer increases with increasing consumption of alcohol on a regular basis.
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The development of nonalcoholic fatty liver disease (NAFLD) is strongly associated with the metabolic syndrome as reflected by the fact that approximately 90% of the patients with NAFLD have more than one feature of metabolic syndrome and about 33% have three or more criteria. The physiopathology, epidemiology and therapeutic considerations of the disease are reviewed here. Lipotoxicity plays a predominant role in the pathophysiology of both entities. It leads to accumulation of triglycerides in the liver as a result of an imbalance among the uptake, synthesis, export, and oxidation of fatty acids. Both conditions are very common in Mexico. Using the Adult Treatment Panel diagnostic criteria, the 1994 prevalence of the metabolic syndrome was 26.6%.Although the prevalence of NAFLD is not known, but it can be estimated from the prevalence of obesity (30%). Since NAFLD is found in over two thirds of the obese subjects, this condition may exist in 20% of the adult population. The treatment of both conditions should be based in an integral approach, including the adoption of a healthy lifestyle, weight loss and may be pharmacotherapy. In summary, NAFLD is the hepatic expression of the metabolic syndrome. The study and treatment of these disorders could not be viewed as separate issues.
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Alcoholic liver disease (ALD) remains a major cause of liver-related mortality in the US and worldwide. The correct diagnosis of ALD can usually be made on a clinical basis in conjunction with blood tests, and a liver biopsy is not usually required. Abstinence is the hallmark of therapy for ALD, and nutritional therapy is the first line of therapeutic intervention. The role of steroids in patients with moderate to severe alcoholic hepatitis is gaining increasing acceptance, with the caveat that patients be evaluated for the effectiveness of therapy at 1 week. Pentoxifylline appears to be especially effective in ALD patients with renal dysfunction/hepatorenal syndrome. Biologics such as specific anti-TNFs have been disappointing and should probably not be used outside of the clinical trial setting. Transplantation is effective in patients with end-stage ALD who have stopped drinking (usually for ≥6 months), and both long-term graft and patient survival are excellent.
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The aim of this study was to investigate mechanisms involved in the growth inhibitory effect of silymarin, in humanhepatocellular carcinoma. The human hepatocellular carcinoma cell line HepG2 was utilized and the MTT assay was performed to study the antiproliferative effect of silymarin. Dual staining was undertaken for ethidium bromide/acridine orange, propidium iodide staining and DNA fragmentation studies were executed to confirm the presence of apoptosis. Cell-cycle analysis was revealed by flow cytometry and mitochondrial transmembrane potential was measured by uptake of the mitochondrial-specific lipophilic cationic dye rhodamine 123. Western blotting analysis for cytochrome c, p53, Bax, Bcl-2, APAF-1, caspase-3, survivin, beta-catenin, cyclin D1, c-Myc and PCNA was carried out. Silymarin inhibited population growth of the hepatocellular carcinoma cells in a dose-dependent manner, and the percentage of apoptotic cells was increased after treatment with 50 and 75 microg/ml silymarin for 24 h. Silymarin treatment increased the proportion of cells with reduced DNA content (sub-G(0)/G(1) or A(0) peak), indicative of apoptosis with loss of cells in the G(1) phase. Silymarin also decreased mitochondrial transmembrane potential of the cells, thereby increasing levels of cytosolic cytochrome c while up-regulating expression of pro-apoptotic proteins (such as p53, Bax, APAF-1 and caspase-3) with concomitant decrease in anti-apoptotic proteins (Bcl-2 and survivin) and proliferation-associated proteins (beta-catenin, cyclin D1, c-Myc and PCNA). Our results demonstrate that silymarin treatment inhibited proliferation and induced apoptosis in the human hepatocellular carcinoma cell line HepG2.
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Background/aims: Several studies have demonstrated that diabetic patients with cirrhosis require insulin treatment because of insulin resistance. As chronic alcoholic liver damage is partly due to the lipoperoxidation of hepatic cell membranes, anti-oxidizing agents may be useful in treating or preventing damage due to free radicals. The aim of this study was to ascertain whether long-term treatment with silymarin is effective in reducing lipoperoxidation and insulin resistance in diabetic patients with cirrhosis. Methods: A 12-month open, controlled study was conducted in two well-matched groups of insulin-treated diabetics with alcoholic cirrhosis. One group (n=30) received 600 mg silymarin per day plus standard therapy, while the control group (n=30) received standard therapy alone. The efficacy parameters, measured regularly during the study, included fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria levels, glycosylated hemoglobin (HbA1c) and malondialdehyde levels. Results: There was a significant decrease (p<0.01) in fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria and HbA1c levels already after 4 months of treatment in the silymarin group. In addition, there was a significant decrease (p<0.01) in fasting insulin levels and mean exogenous insulin requirements in the treated group, while the untreated group showed a significant increase (p<0.05) in fasting insulin levels and a stabilized insulin need. These findings are consistent with the significant decrease (p<0.01) in basal and glucagon-stimulated C-peptide levels in the treated group and the significant increase in both parameters in the control group. Another interesting finding was the significant decrease (p<0.01) in malondialdehyde/levels observed in the treated group. Conclusions: These results show that treatment with silymarin may reduce the lipoperoxidation of cell membranes and insulin resistance, significantly decreasing endogenous insulin overproduction and the need for exogenous insulin administration.
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This report is a summary of a symposium on the role of S-adenosylmethionine (SAM), betaine, and folate in the treatment of alcoholic liver disease (ALD), which was organized by the National Institute on Alcohol Abuse and Alcoholism in collaboration with the Office of Dietary Supplements and the National Center for Complementary and Alternative Medicine of the National Institutes of Health (Bethesda, MD) and held on 3 October 2005. SAM supplementation may attenuate ALD by decreasing oxidative stress through the up-regulation of glutathione synthesis, reducing inflammation via the down-regulation of tumor necrosis factor-alpha and the up-regulation of interleukin-10 synthesis, increasing the ratio of SAM to S-adenosylhomocysteine (SAH), and inhibiting the apoptosis of normal hepatocytes and stimulating the apoptosis of liver cancer cells. Folate deficiency may accelerate or promote ALD by increasing hepatic homocysteine and SAH concentrations; decreasing hepatic SAM and glutathione concentrations and the SAM-SAH ratio; increasing cytochrome P4502E1 activation and lipid peroxidation; up-regulating endoplasmic reticulum stress markers, including sterol regulatory element-binding protein-1, and proapoptotic gene caspase-12; and decreasing global DNA methylation. Betaine may attenuate ALD by increasing the synthesis of SAM and, eventually, glutathione, decreasing the hepatic concentrations of homocysteine and SAH, and increasing the SAM-SAH ratio, which can trigger a cascade of events that lead to the activation of phosphatidylethanolamine methyltransferase, increased phosphatidylcholine synthesis, and formation of VLDL for the export of triacylglycerol from the liver to the circulation. Additionally, decreased concentrations of homocysteine can down-regulate endoplasmic reticulum stress, which leads to the attenuation of apoptosis and fatty acid synthesis.
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Alcoholic Liver Disease (ALD) is a major cause of morbidity and mortality both in the United States and worldwide. In the United States, it is projected that over 2,000,000 persons have ALD, and the mortality for cirrhosis with superimposed alcoholic hepatitis is much worse than that of many common types of cancer. Unfortunately, there is no FDA approved therapy for ALD. We have made major strides in the last decade in identifying mechanisms for the development of liver injury in ALD, and therapies are evolving directed at specific mechanisms. It is clear that life style modification with abstinence, cessation of smoking and weight loss (if overweight) are beneficial. It is also clear that most patients with advanced liver disease have some form of malnutrition, and nutritional supplementation is of benefit. Patients with alcoholic hepatitis that is relatively severe in nature, but not complicated by issues such as infection or GI bleeding, appear to benefit from steroids. A drop in bilirubin should be monitored in steroid treated patients. Pentoxifylline appears to be beneficial in patients with alcoholic hepatitis, especially those with early hepatorenal syndrome. A variety of other agents such as PTU, lecithin, colchicine, and anabolic steroids are probably not effective. Complementary and alternative medicine agents such as zinc, milk thistle, and SAM have great therapeutic rationale. Results of ongoing NIH studies evaluating agents such as specific anti-TNF's, SAM and Milk Thistle are eagerly awaited. Transplantation is clearly an option for end stage ALD in patients who are abstinent.
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Objectives: Aim of this study was to evaluate the effect of Ademethionine therapy on biochemical and clinical parameters and on quality of life in chronic liver disease patients. Methods: Patients affected by chronic hepatitis or compensated liver cirrhosis were included in the open multicenter study. Clinical and biochemical parameters and quality of life scores were recorded at baseline, after 2 weeks of intramuscular Ademethionine administration, and after 6 weeks of oral Ademethionine therapy. Results: 371 patients completed the short term study. Clinical and biochemicals parameters and QoL score improved significantly (p < 0.01). Ninety-nine patients finished the 2-course and 54 the 3-course long-term study. Repeated courses of therapy maintained or improved first course results. QoL improved during treatment, but tended to worsen during wash-out(s). Conclusions: Ademethionine, short- and long-term administration, improved clinical and biochemical parameters and QoL score in chronic liver disease patients.
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Background & aims: Hepatitis C virus (HCV) is the leading aetiological factor of HCC in the western world where, overall, its incidence is increasing, despite data suggesting an initial drop in some areas. The aim of this study was to evaluate epidemiology, clinical features and survival of HCV-related HCC (HCV-HCC) in a wide time range in Italy. Methods: Multicentre retrospective study including 3695 patients prospectively recruited by the ITA.LI.CA group. Patients were classified into three subgroups according to aetiology (Group A[GA], pure HCV; Group B[GB], HCV + cofactors; and Group C[GC], non-HCV) and in 5 time cohorts (5 years each), according to the year of diagnosis. Age, gender, Child-Pugh score, modality of diagnosis, stage, presence of thrombosis/metastases, type of treatment and survival were analysed. Results: A total of 1801 GA patients, 445 GB and 1333 GC were recruited. The number of GA patients peaked in the 1996-2000, gradually dropping thereafter (P < 0.0001), as observed for GB (P < 0.0001). Age at diagnosis increased (P < 0.0001), while percentage of patients diagnosed during surveillance and stage improved only in GA (P = 0.02 and P = 0.003 respectively). The survival significantly increased over time particularly in GA (median 37 months) and was longer in GA than in GB and GC (P < 0.0001). Conclusions: The prevalence of HCC-HCV is decreasing in Italy since 2001. HCV-HCC patients are older, more frequently diagnosed under surveillance and in an earlier stage. HCC survival improved in the last 15 years and is significantly higher in patients with HCV-HCC. We therefore expect a further drop in both incidence and mortality for HCV-HCC in the years to come.
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Non-alcoholic fatty liver disease (NAFLD) is a common occurrence after orthotopic liver transplantation (OLT). The association steatosis/HCV determines important implications for clinical practice: steatosis accelerates the progression of fibrosis and reduces the likelihood of obtaining a sustained virological response (SVR) with antiviral therapy. In post-transplant HCV patients we have evidenced a strong correlation between body mass index (BMI), cholesterol, triglycerides (TGC) and hepatic percentage of steatosis. In subjects with BMI <25 and TGC <160 ng/mL, the chance of SVR was 48 times higher than that of non response. The chances of SVR and sustained biochemical response for patients with percentage of steatosis <15 were 12 times higher than that with higher percentage of steatosis. We can conclude how the amount of steatosis be noted specifically in biopsy examination reports of patients with relapse chronic hepatitis C and how the management of dismetabolism, diet and exercise therapy can improve BMI, liver histology and the response to antiviral therapy.
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Annually, hepatocellular carcinoma is diagnosed in approximately a half-million people worldwide. Based on the association of alcohol with cancer, a International Agency for Research on Cancer working group recently deemed alcoholic beverages "carcinogenic to humans," causally related to occurrence of malignant tumors of the oral cavity, pharynx, larynx, esophagus, liver, colorectum, and female breast. Alcohol metabolism in the liver leads to reactive oxygen species production, induction of activity of cytochrome P450s, and reduction of antioxidants. This review analyzes the epidemiology and pathogenesis of alcohol in hepatocellular cancer.
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Alcoholic beverages have been classified as carcinogenic to humans. As alcoholic beverages are multicomponent mixtures containing several carcinogenic compounds, a quantitative approach is necessary to compare the risks. Fifteen known and suspected human carcinogens (acetaldehyde, acrylamide, aflatoxins, arsenic, benzene, cadmium, ethanol, ethyl carbamate, formaldehyde, furan, lead, 4-methylimidazole, N-nitrosodimethylamine, ochratoxin A and safrole) occurring in alcoholic beverages were identified based on monograph reviews by the International Agency for Research on Cancer. The margin of exposure (MOE) approach was used for comparative risk assessment. MOE compares a toxicological threshold with the exposure. MOEs above 10,000 are judged as low priority for risk management action. MOEs were calculated for different drinking scenarios (low risk and heavy drinking) and different levels of contamination for four beverage groups (beer, wine, spirits and unrecorded alcohol). The lowest MOEs were found for ethanol (3.1 for low risk and 0.8 for heavy drinking). Inorganic lead and arsenic have average MOEs between 10 and 300, followed by acetaldehyde, cadmium and ethyl carbamate between 1,000 and 10,000. All other compounds had average MOEs above 10,000 independent of beverage type. Ethanol was identified as the most important carcinogen in alcoholic beverages, with clear dose response. Some other compounds (lead, arsenic, ethyl carbamate, acetaldehyde) may pose risks below thresholds normally tolerated for food contaminants, but from a cost-effectiveness point of view, the focus should be on reducing alcohol consumption in general rather than on mitigative measures for some contaminants that contribute only to a limited extent (if at all) to the total health risk.
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Inflammation and oxidative stress are associated with liver injury and development of liver disease. The transcription factors nuclear factor-kappa beta (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) play critical roles in modulating liver injury and damage. Activation of NF-κB induces production of pro-inflammatory molecules including prostaglandin E2 (PGE(2) ), interleukin-8 (IL-8) and macrophage chemotactic protein-1 (MCP-1). Nrf2 regulates genes controlling antioxidants. Our laboratory previously showed that hepatocytes, the primary functional cell type comprising liver tissue, respond to the cytokine interleukin-1 beta (IL-1β) by increased production of PGE(2) , IL-8 and MCP-1. This increase is associated with nuclear translocation of NF-κB. In this study, we evaluated whether primary canine hepatocytes pre-treated with the combination of S-adenosylmethionine (SAMe; 30 and 2000 ng/ml) and silybin (SB; 298 ng/ml), agents with known anti-inflammatory and antioxidant properties, could attenuate IL-1β-induced inflammation and oxidative stress. The SAMe and SB combination reduced cytokine-induced PGE(2) , IL-8 and MCP-1 production while also inhibiting NF-κB nuclear translocation. These changes were accompanied by increased antioxidant enzyme-reduced glutathione (GSH) comparable to control levels. The study shows for the first time that the SAMe and SB combination inhibits both inflammation and oxidative stress through two separate signalling pathways.
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S-adenosyl-L-methionine (SAM) is the methyl donor for all methylation reactions and regulates the synthesis of glutathione, the main cellular antioxidant. Previous experimental studies suggested that SAM may benefit patients with established alcoholic liver diseases (ALDs). The aim of this study was to determine the efficacy of SAM in treatment for ALD in a 24-week trial. The primary endpoints were changes in serum aminotransferase levels and liver histopathology scores, and the secondary endpoints were changes in serum levels of methionine metabolites. We randomized 37 patients with ALD to receive 1.2 g of SAM by mouth or placebo daily. Subjects were required to remain abstinent from alcohol drinking. A baseline liver biopsy was performed in 24 subjects, and a posttreatment liver biopsy was performed in 14 subjects. Fasting serum SAM levels were increased over timed intervals in the SAM treatment group. The entire cohort showed an overall improvement of AST, ALT, and bilirubin levels after 24 weeks of treatment, but there were no differences between the treatment groups in any clinical or biochemical parameters nor any intra- or intergroup differences or changes in liver histopathology scores for steatosis, inflammation, fibrosis, and Mallory-Denk hyaline bodies. Whereas abstinence improved liver function, 24 weeks of therapy with SAM was no more effective than placebo in the treatment for ALD.
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Liver fibrosis is the excessive accumulation of extracellular matrix (ECM) components that disrupt normal liver microcirculation and lead to organ injury. Hepatic stellate cells (HSCs), following transdifferentiation, are the central mediators of hepatic fibrosis through increased secretion of ECM components, including type I collagen. The mechanism(s) by which the antioxidant S-adenosyl-L-methionine (SAMe) acts to modulate type I collagen secretion in activated HSCs was examined. Hepatic stellate cells were culture-activated for 13-15 days and treated with SAMe. Type I collagen, proteasomal activity and resident endoplasmic reticulum (ER) protein [78-kDa glucose-regulated protein (Grp78) and protein disulphide isomerase (PDI)] expression were measured. Nuclear factor-κB (NF-κB) activity, and its role in SAMe-mediated collagen inhibition, was determined. Type I collagen polyubiquitination was examined. S-adenosyl-L-methionine significantly inhibited type I collagen secretion without significant changes in type I collagen mRNA expression. SAMe also increased NF-κB activity, and blocking NF-κB activity using a dominant-negative IκBα abolished the SAMe-mediated type I collagen secretion. Examination of the post-transcriptional fate of procollagen demonstrated that SAMe treatment led to intracellular type I collagen polyubiquitination accompanied by diminution of proteasomal activity. Expression of Grp78 and PDI (resident ER proteins) were significantly decreased by SAMe treatment. S-adenosyl-L-methionine inhibits collagen processing leading to increased ubiquitination and decreased secretion. These findings represent a novel mechanism for modulating type I collagen expression in activated HSCs.
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Toll-like receptors (TLR) play a role in mediating the proinflammatory response, fibrogenesis and carcinogenesis in chronic liver diseases such as alcoholic liver disease, non-alcoholic liver disease, hepatitis C and hepatocellular carcinoma. This is true in experimental models of these diseases. For this reason, we investigated the TLR proinflammatory response in the chronic intragastric tube feeding rat model of alcohol liver disease. The methyl donor S-adenosylmethionine was also fed to prevent the gene expression changes induced by ethanol. Ethanol feeding tended to increase the up regulation of the gene expression of TLR2 and TLR4. SAMe feeding prevented this. TLR4 and MyD88 protein levels were significantly increased by ethanol and this was prevented by SAMe. This is the first report where ethanol feeding induced TLR2 and SAMe prevented the induction by ethanol. CD34, FOS, interferon responsive factor 1 (IRF-1), Jun, TLR 1,2,3,4,6 and 7 and Traf-6 were found to be up regulated as seen by microarray analysis where rats were sacrificed at high blood alcohol levels compared to pair fed controls. Il-6, IL-10 and IFNγ were also up regulated by high blood levels of ethanol. The gene expression of CD14, MyD88 and TNFR1SF1 were not up regulated by ethanol but were down regulated by SAMe. The gene expression of IL-1R1 and IRF1 tended to be up regulated by ethanol and this was prevented by feeding SAMe. The results suggest that SAMe, fed chronically prevents the activation of TLR pathways caused by ethanol. In this way the proinflammatory response, fibrogenesis, cirrhosis and hepatocellular carcinoma formation due to alcohol liver disease could be prevented by SAMe.
Article
Silymarin is the most commonly used herbal product for chronic liver disease; yet, whether silymarin protects against liver disease progression remains unclear. To assess the effects of silymarin use on subsequent liver disease progression in 1049 patients of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had advanced fibrosis or cirrhosis and had failed prior peginterferon plus ribavirin treatment. Patients recorded their use of silymarin at baseline and were followed up for liver disease progression (two point increase in Ishak fibrosis score across baseline, year 1.5, and year 3.5 biopsies) and over 8.65 years for clinical outcomes. At baseline, 34% of patients had used silymarin, half of whom were current users. Use of silymarin was associated (P < 0.05) with male gender; oesophageal varices; higher ALT and albumin; and lower AST/ALT ratio, among other features. Baseline users had less hepatic collagen content on study biopsies and had less histological progression (HR: 0.57, 95% CI: 0.33-1.00; P-trend for longer duration of use=0.026). No effect was seen for clinical outcomes. Silymarin use among patients with advanced hepatitis C-related liver disease is associated with reduced progression from fibrosis to cirrhosis, but has no impact on clinical outcomes (Clinicaltrials.gov #NCT00006164).
Article
Alcoholic liver disease (ALD) remains a major cause of morbidity and mortality worldwide. For example, the Veterans Administration Cooperative Studies reported that patients with cirrhosis and superimposed alcoholic hepatitis had a 4-year mortality of >60%. The poor prognosis of ALD implies that preventing disease progression would be more effective than treating end-stage liver disease. An obvious avenue of prevention would be to remove the damaging agent; however, the infamously high rate of recidivism in alcoholics makes maintaining abstinence a difficult treatment goal to prevent ALD. Indeed, although the progression of ALD is well-characterized, there is no universally accepted therapy available to halt or reverse this process in humans. With better understanding of the mechanism(s) and risk factors that mediate the initiation and progression of ALD, rational targeted therapy can be developed to treat or prevent ALD. The purpose of this review is to summarize the established and proposed mechanisms by which chronic alcohol abuse damages the liver and to highlight key signaling events known or hypothesized to mediate these effects.
Article
Continued hazardous and harmful drinking can result in dependence and tolerance, with risk of alcohol withdrawal syndrome on abrupt reduction or cessation; it may also result in damage to almost any organ or system in the body. Hazardous and harmful drinkers are commonly encountered among hospital patients, with 863 300 alcohol related admissions to hospital in 2007-8, an increase of 69% since 2002-3.1 The cost to the NHS of treating acute and chronic drinking is estimated to be as much as £2.7bn a year.2 This article summarises recommendations made in the recent guidance from the National Institute for Health and Clinical Excellence (NICE) for the diagnosis and clinical management of alcohol related physical complications in adults and children (aged over 10 years).3 That guideline should be read in conjunction with the NICE public health guidance on the prevention and early identification of alcohol use disorders in adults and young people4 and the forthcoming NICE clinical guideline on the management of alcohol dependence and harmful alcohol use.5 NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Development Group’s experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets. ### Acute alcohol withdrawal #### Admission to hospital
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Evaluation of the interaction between alcohol intake and cofactors [hepatitis B virus (HBV), hepatitis C virus (HCV), body mass index] and coffee consumption on the risk of cirrhosis. Seven hundred and forty-nine consecutive patients with chronic liver disease referring to units for liver or alcohol diseases in Italy during a 6-months period. Teetotalers were excluded. The odds ratios (OR) for cirrhosis were evaluated using chronic hepatitis cases as the control group. An alcohol intake of more than 3 units/day resulted associated with the likelihood of cirrhosis both in males (OR 4.3; 95% CI=2.5-7.3) and in females (OR 5.7; 95% CI=2.3-14.5). A multiplicative interaction on the risk of cirrhosis between risky alcohol intake and HBsAg or HCV-Ab/HCV-RNA positivity was observed. A reduction of cirrhosis risk was observed in subjects consuming more than 3 alcohol units/day with increasing coffee intake. The OR for the association with cirrhosis decreased from 2.3 (95% CI=1.2-4.4) in subjects drinking 0-2 cups of coffee/day to 1.4 (95% CI=0.6-3.6) in those drinking more than 2 cups/day. In subjects with an alcohol intake >3 units/day the coexistence of HBV or HCV multiplies the risk of cirrhosis. Coffee represents a modulator of alcoholic cirrhosis risk.
Article
Up to today no work has evaluated yet the importance of parameters such Body Mass Index (BMI), cholesterol, triglycerides (TGC) and hepatic percentage of steatosis in the response to therapy with Pegylated Interferon Alfa-2a and Ribavirin in patients with recurrent hepatitis C (genotype 1). 30 consecutive prospectively followed patients diagnosed with recurrent HCV were considered candidates for antiviral therapy. Qualitative and quantitative detection of HCV-RNA was performed with the Cobas Amplicor Hepatitis C Virus Test, version 2.0 and the Cobas Amplicor HCV Monitor, version 2.0 (Roche Diagnostics, Branchburgh, NJ, U.S.A.). HCV genotyping was performed by sequencing of the 5 untraslated region (5' UTR) (Visible Genetics TruGene Hepatitis Assay, Toronto, Canada). The observed distribution of BMI, cholesterol, TGC and steatosis were confirmed to be normally distributed by the one-sample Kolmogorov-Smirnov Goodness of fit test procedure. Comparison of BMI, cholesterol, TGC and steatosis between non responders (NR), sustained virological responders (SVR) and sustained biochemical responders (SBR) groups were analyzed by ANOVA with a post hoc Bonferroni test and correlation between variables was tested by Pearson test. The multivariate analysis was performed to estimate the chance of response on basis of the above mentioned variables. In patients with abnormal results in at least two out of four considered variables the chance of no-response was 40 times higher than that of SBR and 96 times than that of SVR. We can conclude how the management of dismetabolism, diet and exercise therapy can improve BMI, liver histology and, therefore, the response to PEG-IFN Alfa-2a and Ribavirin.
Article
Alteration in intestinal permeability may be an important factor in the pathogenesis of both the progression of some chronic liver diseases and the onset of some complications in patients with liver cirrhosis. To investigate the relationships between intestinal permeability, portal hypertension, alcohol use, plasma levels of pro-inflammatory cytokines, and nitric oxide, expressed as s-nitrosothiols, and nitrite levels in patients with various types and degrees of chronic liver diseases. 134 healthy volunteers and 83 patients with chronic liver damage entered the study. Intestinal permeability was assessed with the lactulose/mannitol test. Plasma levels of tumour necrosis factor-alpha, interleukin-6, and nitrite and total s-nitrosothiols were determined. Intestinal permeability was altered in patients with advanced liver disease and impaired in 15-35% of patients without cirrhosis. Independent factors for intestinal permeability alteration were age, portal hypertension, alcohol use, and diabetes. Plasma levels of inflammatory cytokines and nitrosothiols were significantly higher in patients with altered intestinal permeability. An intestinal permeability evaluation in patients with chronic liver diseases might clarify the significance of intestinal permeability in the pathophysiology of both the progression of liver damage, and the occurrence of complications that accompany liver cirrhosis.
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Hepatic fibrogenesis, a consequence of chronic liver tissue damage, is characterized by activation of the hepatic stellate cells (HSC). Silybin has been shown to exert anti-fibrogenic effects in animal models. However, scant information is available on the fine cellular and molecular events responsible for this effect. The aim of this study was to assess the mechanisms regulating the anti-fibrogenic and anti-inflammatory activity of Silybin. Experiments were performed on HSC isolated from human liver and activated by culture on plastic. Silybin was able to inhibit dose-dependently (25-50 microM) growth factor-induced pro-fibrogenic actions of activated human HSC, including cell proliferation (P < 0.001), cell motility (P < 0.001), and de novo synthesis of extracellular matrix components (P < 0.05). Silybin (25-50 microM), inhibited the IL-1-induced synthesis of MCP-1 (P < 0.01) and IL-8 (P < 0.01) showing a potent anti-inflammatory activity. Silybin exerts its effects by directly inhibiting the ERK, MEK and Raf phosphorylation, reducing the activation of NHE1 (Na+/H+ exchanger, P < 0.05) and the IkBalpha phosphorylation. In addition, Silybin was confirmed to act as a potent anti-oxidant agent. The results of the study provide molecular insights into the potential therapeutic action of Silybin in chronic liver disease. This action seems to be mostly related to a marked inhibition of the production of pro-inflammatory cytokines, a clear anti-oxidant effect and a reduction of the direct and indirect pro-fibrogenic potential of HSC.
Article
Silymarin, the active principle of the milk thistle Silybum marianum, protects experimental animals against various hepatotoxic substances. To determine the effect of silymarin on the outcome of patients with cirrhosis, a double blind, prospective, randomized study was performed in 170 patients with cirrhosis. 87 patients (alcoholic 46, non-alcoholic 41; 61 male, 26 female; Child A, 47; B, 37; C, 3; mean age 57) received 140 mg silymarin three times daily. 83 patients (alcoholic 45, non-alcoholic 38; 62 male, 21 female; Child A, 42; B, 32; C, 9: mean age 58) received a placebo. Non-compliant patients and patients who failed to come to a control were considered as 'drop outs' and were withdrawn from the study. All patients received the same treatment until the last patient entered had finished 2-years of treatment. The mean observation period was 41 months. There were 10 drop outs in the placebo group and 14 in the treatment group. In the placebo group, 37 (+2 drop outs) patients had died, and in 31 of these, death was related to liver disease. In the treatment group, 24 (+4 drop outs) had died, and in 18 of these, death was related to liver disease. The 4-year survival rate was 58 +/- 9% (S.E.) in silymarin-treated patients and 39 +/- 9% in the placebo group (P = 0.036). Analysis of subgroups indicated that treatment was effective in patients with alcoholic cirrhosis (P = 0.01) and in patients initially rated 'Child A' (P = 0.03). No side effects of drug treatment were observed.(ABSTRACT TRUNCATED AT 250 WORDS)
In order to assess the liver protective activity and the antioxidant properties of a new silybin complex (IdB1016), we carried out a short-term pilot study on 20 patients with chronic active hepatitis (CAH), randomly assigned to 240 mg of silybin b.i.d. (10 patients, 4 m/6 f, mean age: 50 years) or placebo (10 patients, 2 m/8 f, mean age: 55 years). Blood samples were collected before and after 7 days of treatment for liver function tests (LFTs), malonaldehyde (MDA) as an index of lipid peroxidation, and copper (Cu) and zinc (Zn), two trace elements involved in protecting cells against free radical-mediated lipid peroxidation. In the treated group, there was a statistically significant reduction of mean (+/- SEM) serum concentrations of aspartate aminotransferase (AST) from 88.0 (+/- 13.3) to 65.9 (+/- 7.5) u/l, (p < 0.01), of alanine aminotransferase (ALT) from 115.9 (+/- 12.9) to 82.5 (+/- 10.6) u/l (p < 0.01), of gamma-glutamyltranspeptidase (gamma-GT) from 51.4 (+/- 9.3) to 41.3 (+/- 4.2) u/l (p < 0.02) and of total bilirubin (TB) from 0.76 (+/- 0.08) to 0.53 (+/- 0.04) mg/dl (p < 0.05). Alkaline phosphatase (AP) fell slightly from 143.4 (+/- 6.4) to 137.5 (+/- 7.8) u/l. There were no significant changes in MDA, Cu or Zn serum concentrations. These results show that IdB1016 may improve LFTs related to hepatocellular necrosis and/or increases membrane permeability in patients affected by CAH.
Article
The efficacy of S-adenosylmethionine (AdoMet) in the treatment of liver cell injury has been demonstrated in several experimental models. The aim of this study was to investigate the effects of AdoMet treatment in human alcoholic liver cirrhosis. A randomized, double-blind trial was performed in 123 patients treated with AdoMet (1200 mg/day, orally) or placebo for 2 years. All patients had alcoholic cirrhosis, and histologic confirmation of the diagnosis was available in 84% of the cases. Seventy-five patients were in Child class A, 40 in class B, and 8 in class C. Sixty-two patients received AdoMet and 61 received placebo. At inclusion into the trial no significant differences were observed between the two groups with respect to sex, age, previous episodes of major complications of cirrhosis, Child classification and liver function tests. The overall mortality/liver transplantation at the end of the trial decreased from 30% in the placebo group to 16% in the AdoMet group, although the difference was not statistically significant (p = 0.077). When patients in Child C class were excluded from the analysis, the overall mortality/liver transplantation was significantly greater in the placebo group than in the AdoMet group (29% vs. 12%, p = 0.025), and differences between the two groups in the 2-year survival curves (defined as the time to death or liver transplantation) were also statistically significant (p = 0.046). The present results indicate that long-term treatment with AdoMet may improve survival or delay liver transplantation in patients with alcoholic liver cirrhosis, especially in those with less advanced liver disease.
Article
Hepatic deficiency of S-adenosylmethionine (AdoMet) is a critical acquired metabolic abnormality in alcoholic liver disease (ALD) and in many experimental models of hepatotoxicity. Subnormal AdoMet, elevated serum tumor necrosis factor (TNF), and endotoxemia (LPS) are hallmarks of ALD and experimental liver injury. AdoMet deficiency is attributed to its subnormal synthesis, but mechanisms for increased TNF are not known. AdoMet deficiency may affect the critical balance of proinflammatory (e.g., TNF) and antiinflammatory [e.g., interleukin (IL)-10] cytokines. Rats maintained on a choline-deficient diet with limited amounts of methionine (MCD diet) developed AdoMet deficiency. When challenged with LPS, rats fed MCD diet had significantly increased serum TNF levels and worse liver injury compared with findings for controls. Exogenous AdoMet attenuated liver injury and serum TNF levels. Results of in vitro studies with the use of RAW 264.7 cells demonstrated that exogenous AdoMet supplementation lowered LPS-induced TNF formation in a dose-dependent manner, and AdoMet deficiency enhanced TNF secretion and TNF gene expression. AdoMet also dose-dependently decreased LPS-stimulated TNF production from monocytes obtained from patients with alcoholic hepatitis. Finally, AdoMet supplementation stimulated production of the antiinflammatory cytokine IL-10. Interleukin-10 plays a critical role in the modulation of TNF production, and IL-10 may inhibit hepatic fibrosis. This article will review (1) the role of AdoMet in ALD/liver injury, (2) the role of TNF/proinflammatory cytokines in ALD, (3) potential roles of AdoMet in TNF/proinflammatory cytokine regulation in ALD, and (4) conclusions and future directions.
Article
TIPS (transjugular intrahepatic portosystemic stent-shunt) has been used increasingly in the management of refractory variceal bleeding. Its role in the management of refractory ascites and hepatorenal syndrome still awaits further prospective studies. Type-2 hepatorenal syndrome is a moderate steady renal impairment. It arises spontaneously and it is the main mechanism of refractory ascites. Precipitating factors may lead to type-1 hepatorenal syndrome. Hepatorenal syndrome is a common complication of advanced cirrhosis with a 3-month mortality of more than 90% unless treated by orthotopic liver transplantation. However, because of the short survival of patients with hepatorenal syndrome and the limited availability of organs, only a small percentage of patients with hepatorenal syndrome can actually reach orthotopic liver transplantation. That is why awaiting orthotopic liver transplantation we have submitted some suitable patients to a TIPS setting. We have considered eighteen consecutive patients affected by advanced cirrhosis (Child-Pugh 10-12) awaiting orthotopic liver transplantation and suitable for TIPS treatment for the presence of type-2 hepatorenal syndrome (10 males, average age 44.5). The criteria for the diagnosis of hepatorenal syndrome and refractory ascites have been effected according to a consensus recommendation. Organic kidney disease was excluded. After mild intravenous sedation and analgesia a puncture needle was advanced transjugular in a catheter through the inferior cava into one of the three hepatic veins. Subsequently, an intrahepatic branch of the portal vein was punctured and the shunt was established by the implantation of Wallstent (diameter 10 mm; Boston, Scientific, Natick, MA). In all patients, we compared serum creatinine, creatinine-clearance, sodium excretion and urine volume before the intervention and 12 weeks after TIPS. The differences among groups were analyzed using paired Student's t-test. The stent shunt was successfully established in all eighteen patients. Complications occurred in 4 patients (temperature above 38 degrees C or vomiting). No patients have developed hepatic encephalopathy resistant to medical treatment. As for the ascites a complete response with total remission of ascites was obtained in eight patients, while a partial response with the presence of sonographically detectable ascites--without the need of paracentesis--was obtained in ten patients. As regards renal functional parameters we have evidenced a significant improvement after TIPS. We can notice how the setting of TIPS, at least in the presented case, has allowed the treatment of ascites and, furthermore, has lead to improvement of the renal functional parameters. It all implies the enormous advantage of a better management of the patient waiting for orthotopic liver transplantation and, most of all, the advantage of preparing the patient for the surgical intervention with normal renal functional parameters: in fact, it is well known that the increase of serum creatinine influences the pre- and post-orthotopic liver transplantation course, and in particular can modify the mortality rate of the patient list. The lack of effective alternative treatment modalities and the almost universally fatal outcome of hepatorenal syndrome make TIPS an attractive option in the treatment of hepatorenal syndrome as a bridge to orthotopic liver transplantation.
Article
Abnormal methionine metabolism occurs in animals fed ethanol and in end-stage cirrhotic patients. Expected consequences of these abnormalities include reduced hepatic S-adenosylmethionine and glutathione (GSH) levels, impaired transmethylation, and reduced homocysteine catabolism, resulting in the often-observed hyperhomocystinemia in cirrhotic patients. These parameters have not been examined simultaneously in patients with less advanced alcoholic liver disease. Six patients hospitalized for alcoholic hepatitis were studied. Plasma was analyzed for homocysteine, methionine, and GSH levels. Liver biopsies diagnosed acute alcoholic hepatitis and underlying fibrosis. Liver specimens were processed for messenger RNA (mRNA) levels and various metabolites and were compared with those of six normal controls. Three patients had cirrhosis, and three had only portal fibrosis. Plasma levels of homocysteine and methionine were increased in two of the three patients with cirrhosis but not in the patients with fibrosis. All patients had markedly lower plasma GSH levels (mean +/- SD: 0.27 +/- 0.19 microM, which is at least 10-fold lower than the normal range). Hepatic S-adenosylmethionine levels were reduced by 50%, whereas methionine, GSH, and cysteine levels were reduced by 70-80%. The mRNA levels of most enzymes involved in methionine metabolism and GSH synthesis were decreased, whereas albumin expression was unchanged. Despite the well known induction of cytochrome P450 2E1 in chronic alcoholics, its mRNA levels were nearly 70% lower in these patients. In alcoholic hepatitis, abnormal hepatic gene expression in methionine and GSH metabolism occurs and often contributes to decreased hepatic methionine, S-adenosylmethionine, cysteine, and GSH levels. It may be important to replenish these thiols in patients hospitalized with alcoholic hepatitis.
Article
An overdose of acetaminophen (APAP) is the most frequent cause of fulminant liver failure in the United States. Increasing evidence demonstrates that oxidative stress plays an important etiologic role in APAP-induced liver injury. S-Adenosylmethionine (SAMe) is a key intermediate in the hepatic trans-sulfuration pathway and serves as a precursor for glutathione (GSH) as well as the methyl donor in most transmethylation reactions. In the present study, we investigated effects of SAMe on liver injury induced by APAP administration in male C57BL/6 mice. Two related studies were performed. In the first experiment, SAMe (1g/kg BW) was injected intraperitoneally 4 h before APAP (600 mg/kg BW) administration. In the second experiment, SAMe was injected intraperitoneally 1 h after APAP administration. Our results showed that APAP administration induced changes typical of confluent centrilobular necrosis by histological examination and a marked elevation in serum alanine aminotransferase (ALT) activity. APAP administration induced significant decreases in both hepatic and blood SAMe concentrations. In addition, APAP decreased intracellular (both cytosolic and mitochondrial) GSH concentrations along with increased lipid peroxidation in conjunction with mitochondrial dysfunction as documented by Ca2+-induced mitochondrial permeability transition. SAMe treatment (both before and after APAP) significantly attenuated the liver injury. Exogenous SAMe prevented the decrease in liver and blood SAMe concentrations. Moreover, SAMe treatment attenuated both cytosolic and mitochondrial GSH depletion as well as mitochondrial dysfunction. We conclude that SAMe at least in part protects the liver from APAP-induced injury by preventing intracellular GSH depletion and mitochondrial dysfunction.
Article
To define the characteristics of the Italian patient presenting non-alcoholic fatty liver disease. A total of 305 patients with abnormally high plasma aminotransferase and/or gamma-glutamyl-transpeptidase levels for at least 12 months, with no known cause of chronic liver damage, were consecutively enrolled in the study. Clinical, routine biochemical and liver histology investigations were carried out in all patients. Also evaluated were: (a) oral glucose load; (b) insulinaemia and insulin-resistance using the HOMA test model; and (c) plasma endotoxaemia, total antioxidant plasma capability, tumour necrosis factor-alpha, plasma interleukin-6 and -10 levels. Malondialdehyde and 4-hydroxynonenal content were determined on liver samples from 120 patients. The majority of patients were young overweight or obese males, with dyslipidaemia (20-60%), diabetes (10.5%), hyperinsulinaemia (40%), hyperferritinaemia (35%). Endotoxaemia was negative in all patients and cytokines were only sporadically altered. Total antioxidant plasma capability was decreased in 38.4% of the patients. Eighty percent of the cases had histological steatosis with a mild degree of inflammation and fibrosis. Seven patients had cirrhosis. Lipid peroxidation markers were increased in 90% of the cases, inversely correlated with fibrosis. Even if at univariate analysis, age, ferritin and tissue 4-hydroxynonenal were independent factors of steatosis (P < 0.01), and insulin, HOMA and ferritin of inflammation and fibrosis (P < 0.01), at multivariate analysis no single factor was found to be an independent predictor of hepatic lesions. The typical Italian patient with non-alcoholic fatty liver disease is a young male, obese, not diabetic, with a variable incidence of dyslipidaemia and hyperinsulinaemia. Only liver biopsy may define the type of liver damage.
Article
Silymarin from the milk thistle herb (Silybum marianum) is used by many patients with chronic viral hepatitis, but its efficacy remains unknown. We performed a systematic review of silymarin for the treatment of chronic viral hepatitis B and C. An exhaustive search strategy identified 148 papers that studied silymarin compounds in liver disease. Of these, four trials included patients with hepatitis C, one included hepatitis B patients, and two, unspecified chronic viral hepatitis. However, only one trial exclusively studied patients with hepatitis C, and none involved patients with only hepatitis B. Silymarin treatment resulted in a decrease in serum transaminases compared with baseline in four studies, and compared with placebo in only one study. There is no evidence that silymarin affects viral load or improves liver histology in hepatitis B or C. No studies were found that investigated the use of silymarin concomitantly with interferon, nucleoside analogues, or other conventional treatments for hepatitis B or C. In conclusion, silymarin compounds likely decrease serum transaminases in patients with chronic viral hepatitis, but do not appear to affect viral load or liver histology. Nevertheless it may be worthwhile to determine its effects in conjunction with standard antiviral treatment.
Article
Steatosis and hepatitis C are two common liver diseases. Epidemiological and experimental data indicate that hepatitis C predisposes to non alcoholic fatty liver disease and the prevalence of coexistent hepatitis C and steatosis is two-three times higher than it would be expected if these were completely independent processes. Two conditions have been defined in course of hepatitis C: the "metabolic fat", characterized by a correlation between steatosis and metabolic alterations and the "viral fat", characterized by a direct action of HCV. Actually, "mixed forms" are often present. Up to today, most of the authors believe that the presence of steatosis accelerates the progression of fibrosis, and therefore the progression to cirrhosis, increases the risk of developing hepatocellular carcinoma, and decreases the antiviral therapy response percentage. The treatment must associate the common antiviral therapy with all the measures fit for facing the metabolic problems, with particular reference to the antioxidant therapy.
Article
Milk thistle (Silybum marianum (L) Gaertneri) extracts have been used as medical remedies since the time of ancient Greece. Alcohol and hepatotoxic viruses are the major causes of liver diseases. Several trials have studied the effects of milk thistle for patients with liver diseases. This systematic review could not demonstrate significant effects of milk thistle on mortality or complications of liver diseases in patients with alcoholic and/or hepatitis B or C liver diseases combining all trials or high-quality trials. Low-quality trials suggested beneficial effects. High-quality randomised clinical trials on milk thistle versus placebo are needed.
Article
The goal of this study was to examine the effect of a standardized silybin and soy phosphatidylcholine complex (IdB 1016) on serum markers of iron status. Milk thistle and its components are widely used as an alternative therapy for liver disease because of purported antioxidant, anti-inflammatory, and iron chelating properties. Thirty-seven patients with chronic hepatitis C and Batts-Ludwig fibrosis stage II, III, or IV were randomized to 1 of 3 doses of IdB 1016 for 12 weeks. Serum ferritin, serum iron, total iron binding capacity, and transferrin-iron saturation were measured at baseline, during treatment, and 4 weeks thereafter. Wilcoxon signed rank tests were used to compare baseline and posttreatment values. There was a significant decrease in serum ferritin from baseline to end of treatment (mean, 244 vs. 215 mug/L; median, 178 vs. 148 mug/L; P=0.0005); 78% of subjects had a decrease in serum ferritin level. There was no significant change in serum iron or transferrin-iron saturation. Multivariate logistic regression analysis in a model that included dose, age, sex, HFE genotype, history of alcohol use, and elevated baseline ferritin levels demonstrated that stage III or IV fibrosis was independently associated with decreased posttreatment serum ferritin level. Treatment with IdB 1016 is associated with reduced body iron stores, especially among patients with advanced fibrosis stage.
Article
Alcohol damages every organ and system in the body. The most important effects from a clinical point of view relate to diseases of the circulatory, nervous and hepato-gastrointestinal systems. In the digestive tract the effects range from increased intestinal transit time and gastrophaties, leading to classical early morning nausea and diarrhea, through to significant malabsorption and chronic pancreatitis. In this review the mechanisms of alcoholic damage have been evaluated with particular reference to alcoholic liver disease (ALD). In particular, the natural history, the influence due to host genetic susceptibility and due to cofactors (i.e. hepatitis C virus), the clinical features and the hepatocarcinogenesis mechanisms have been evaluated. Finally, a possible role of abstinence in association with pharmacological therapy in the course of steatohepatitis has also been evaluated.