Vitamin E improves the aminotransferase status of patients suffering from viral hepatitis C: a randomized, double-blind, placebo-controlled study. A randomized placebo controlled trial of vitamin E for alcoholic hepatitis. Management of fatty liver disease with vitamin E and C compared to ursodeoxycholic acid treatment. Identifying outcome reporting bias in randomised trials on PubMed: review of publications and survey of authors Oxidative-inflammatory damage in cirrhosis: effect of vitamin E and a fermented papaya preparation. The effect of antioxidant supplementation on a serum marker of free radical activity and abnormal serum biochemistry in alcoholic patients admitted for detoxification. Vitamin A treatment of sexual dysfunction in male alcoholics. Pilot clinical trial of the use of alpha-tocopherol for the prevention of hepatocellular carcinoma in patients with liver cirrhosis. Evidence at a glance: error matrix approach for overviewing available evidence Does ascorbic acid prevent retinopathy during interferon therapy in patients with chronic hepatitis C? Pilot study on the effect of parenteral vitamin E on ischemia and reperfusion induced liver injury: a double blind, randomized, placebo-controlled trial. Interferon/antioxidant combination therapy for chronic hepatitis C--a controlled pilot trial. Literature searching for randomized controlled trials used in Cochrane reviews: rapid versus exhaustive searches. Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles. Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong The effect of antioxidant supplementation on hepatitis C viral load, transaminases and oxidative status: a randomized trial among chronic hepatitis C virus-infected patients Vitamin E as treatment for chronic hepatitis B: results of a randomized controlled pilot trial. Changes in Serum Retinol, α-Tocopherol, Vitamin C, Carotenoids, Zinc and Selenium after Micronutrient Supplementation during Alcohol Rehabilitation Methods for combining randomized clinical trials: strengths and limitations. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. Effects of long-term vitamin E supplementation in alcoholic cirrhotics. [Alcohol-induced toxic hepatitis--a "free radical" associated disease. Lowering fatality by adjuvant antioxidant therapy]. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis Routine Vitamin Supplementation To Prevent Cancer and Cardiovascular Disease: Recommendations and Rationale Oral antioxidant supplementation for fatigue associated with primary biliary cirrhosis: results of a multicentre, randomized, placebo‐controlled, cross‐over trial A Randomized Controlled Trial of Metformin versus Vitamin E or Prescriptive Diet in Nonalcoholic Fatty Liver Disease High‐dose vitamin E supplementation does not diminish ribavirin‐associated haemolysis in hepatitis C treatment with combination standard α‐interferon and ribavirin Antioxidant drugs combined with alpha-interferon in chronic hepatitis C not responsive to alpha-interferon alone: a randomized, multicentre study. Improvement of hemorheological abnormalities in alcoholics by an oral antioxidant. Antioxidant therapy for chronic hepatitis C after failure of interferon: results of phase II randomized, double-blind placebo controlled clinical trial. Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension. Treatment of Chronic Hepatitis C Virus Infection via Antioxidants: Results of a Phase I Clinical Trial Low selenium status in alcoholic cirrhosis is correlated with aminopyrine breath test Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Tissue thiamin levels of hospitalised alcoholics before and after oral or parenteral vitamins. A pilot study of the effects of d-alpha-tocopherol on hepatic stellate cell activation in chronic hepatitis C. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. A randomized trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis. Antioxidant and immunomodulatory effects of Viusid in patients with chronic hepatitis C. Vitamin E and C supplementation prevents decrease of eicosapentaenoic acid in mononuclear cells in chronic hepatitis C patients during combination therapy of interferon alpha-2b and ribavirin. Antioxidants versus corticosteroids in the treatment of severe alcoholic hepatitis--a randomised clinical trial.
UNLABELLED Vitamin E has been shown to protect against liver damage induced by oxidative stress in animal experiments . Based on our previous findings of diminished vitamin E levels in patients suffering from viral hepatitis , we treated 23 hepatitis C patients refractory to alpha-interferon therapy  with high doses of vitamin E ( 2 x 400 IU RRR-alpha-tocopherol/day ) for 12 weeks . STUDY DESIGN pro-spective r and omized double-blind crossover design . Clinical parameters including alanine aminotransferase ( ALT ) and aspartate aminotransferase ( AST ) were determined for monitoring the disease state , in parallel  vitamin E plasma levels and plasma lipids were determined . The plasma levels of the alpha-tocopherol  were increased about 2-fold in all 23 patients . In 11 of 23 patients the clinical parameters indicative of liver damage were improved during the phase of vitamin E treatment ( 48 % responders ) . ALT levels in responders were lowered by 46 % and AST levels were lowered by 35 % after 12 weeks of vitamin E treatment . Cessation of vitamin E treatment was followed by a rapid relapse of ALT and AST elevation , whereas retreatment led to a reproducible ALT decrease by 45 % and AST decrease of 37 % after a 6 months followup . Since vitamin E is non-toxic even at elevated doses ingested over extended periods , we suggest the treatment of patients refractory to alpha-interferon therapy  suffering from hepatitis C with vitamin E as a supportive therapy BACKGROUND / AIMS The effect of vitamin E administration on clinical and laboratory parameters of liver function and on markers of fibrogenesis was assessed in patients with mild to moderate alcoholic hepatitis in a double blind placebo controlled r and omized trial . METHODS Twenty-five patients received 1000  I.U.  of vitamin E per day , while 26 patients received placebo for 3 months . The patients were followed for 1 year after entry into the trial . RESULTS Vitamin E did not result in significant greater decreases in serum aminotransferases and serum bilirubin or in greater increases in serum albumin as compared with placebo .  Prothrombin time did not change , while serum creatinine remained in the normal range . Monocyte nuclear nuclear factor-kappa B binding activity decreased in patients who remained abstinent , regardless of whether they received vitamin E. As regards markers of hepatic fibrogenesis , vitamin E treatment decreased serum hyaluronic acid ( P<0.05 ) while serum aminoterminal peptide of type III procollagen did not change in either group . Four patients in the treatment group and five in the placebo group died during the 1-year study . CONCLUSIONS Vitamin E treatment improves serum hyaluronic acid but has no beneficial effects on tests of liver function in patients with mild to moderate alcoholic hepatitis BACKGROUND / AIMS Despite a proposed role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis , antioxidant approaches have not been investigated sufficiently in the therapy of nonalcoholic steatohepatitis . Our aim was to determine whether vitamin E plus C therapy is effective in normalization of liver enzymes compared to ursodeoxycholic acid treatment in patients with fatty liver disease . METHODS This was an open-labeled , prospect i ve , r and omized study enrolling patients with histologically proven fatty liver disease who had chronically elevated alanine aminotransferase , despite a three-month reducing diet . Patients consuming alcohol ( more than 20 g/day ) were excluded . The patients were r and omly prescribed either oral vitamin E ( 600 IU/day ) plus vitamin C ( 500 mg/day ) or ursodeoxycholic acid ( 10 mg/kg/day ) . Patients were r and omized as two groups to receive vitamin E plus vitamin C combination ( 28 patients , 10 F ) or ursodeoxycholic acid treatment ( 29 patients , 13 F ) . RESULTS There was no significant change in body mass index before and after the treatment in both groups . At the end of six months of therapy , serum aspartate aminotransferase and aminotransferase levels significantly decreased in both treatment options . Vitamin E and C combination was more efficacious on serum aminotransferase levels than ursodeoxycholic acid , but the difference was not significant . Alanine aminotransferase decreased to normal levels in 17 of 27 ( 63 % ) and in 16 of 29 patients ( 55 % ) , respectively , in the two groups . Gamma-glutamyl transpeptidase decreased in patients receiving ursodeoxycholic acid , but no change was obtained in the vitamin-treated patients . CONCLUSIONS Vitamin E plus C combination treatment is a safe , inexpensive and effective treatment option in patients with fatty liver disease , with results comparable to those obtained with ursodeoxycholic acid . Since more effective new therapeutic options are lacking , patients with fatty liver disease should be encouraged to take vitamin E and C supplements , which are safe and affordable Abstract Objective To examine the extent and nature of outcome reporting bias in a broad cohort of published r and omised trials . Design Retrospective review of publications and follow up survey of authors . Cohort All journal articles of r and omised trials indexed in PubMed whose primary publication appeared in December 2000 . Main outcome measures Prevalence of incompletely reported outcomes per trial ; reasons for not reporting outcomes ; association between completeness of reporting and statistical significance . Results 519 trials with 553 publications and 10 557 outcomes were identified . Survey responders ( response rate 69 % ) provided information on unreported outcomes but were often unreliable — for 32 % of those who denied the existence of such outcomes there was evidence to the contrary in their publications . On average , over 20 % of the outcomes measured in a parallel group trial were incompletely reported . Within a trial , such outcomes had a higher odds of being statistically non-significant compared with fully reported outcomes ( odds ratio 2.0 ( 95 % confidence interval 1.6 to 2.7 ) for efficacy outcomes ; 1.9 ( 1.1 to 3.5 ) for harm outcomes ) . The most commonly reported reasons for omitting efficacy outcomes included space constraints , lack of clinical importance , and lack of statistical significance . Conclusions Incomplete reporting of outcomes within published articles of r and omised trials is common and is associated with statistical non- significance . The medical literature therefore represents a selective and biased subset of study outcomes , and trial protocol s should be made publicly available BACKGROUND AND AIM Oxidative DNA damage occurs as an early event in hepatitis C virus ( HCV ) infection and is an indication of the potential for carcinogenesis . The aim of this study was to test a novel antioxidant/immunomodulator in patients with HCV-related cirrhosis . METHODS The study group consisted of 50 patients with HCV-related cirrhosis with transaminase values less than twofold increased ( alanine aminotransferase [ ALT ] < 80 IU/L ) . Patients underwent a st and ardized food-vitamin composition assessment and were assessed for dietary intake , nutritional status and iron level . Patients were r and omly allocated into two groups and then given either alpha-tocopherol 900 IU/day or 9 g/day of a fermented papaya preparation ( FPP , Immun-Age , Osato Research Institute , Gifu , Japan ) at bedtime for 6 months . Ten healthy subjects served as controls . Patients were checked monthly for : routine tests , redox status ( reduced glutathione , glutathione peroxidase , oxidized glutathione , malondialdehyde ) , plasma alpha-tocopherol , 8-hydroxy-deoxy-guanidine ( 8-OHdG ) level in circulating leukocyte DNA and serum levels of cytokines . RESULTS Patients with cirrhosis showed a significant imbalance of redox status ( low antioxidants/high oxidative stress markers ) ( P < 0.005 vs controls ) . Neither treatment regimen affected transaminases as a whole . However , vitamin E supplementation almost normalized ALT only in the limited vitamin-E-deficient subgroup . A significant improvement of redox status was obtained by both regimens . However , only FPP significantly decreased 8-OHdG and the improvement of cytokine balance with FPP was significantly better than with vitamin E treatment ( P < 0.05 ) . CONCLUSIONS Although the present data seem to suggest a potential supportive role of antioxidants/immunomodulators as FPP in HCV patients , more studies are needed to substantiate their effect on the natural history of the disease Alcoholics admitted for detoxification were entered into a double blind placebo controlled trial of oral supplementation with an antioxidant cocktail ( vitamin E , beta carotene , vitamin C and selenium ) in order to determine the effect of this supplementation on the rate of resolution of a serum marker of free radical activity and abnormal serum biochemistry . The molar proportion of linoleic acid that was diene conjugated ( a marker of free radical activity ) , was increased in the alcoholics 2.9 % + /- 1.2 ( mean + /- S.D. ) compared to normal controls 1.3 % + /- 0.6 ( P < 0.0001 ) but fell at a similar rate during the first week of hospitalisation in supplemented and placebo-treated patients with a mean fall of 53.7 % ( + /- 16.4 S.D. ) in the placebo group and 56.0 % ( + /- 23.7 ) ( P = 0.32 , NS ) in the antioxidant supplemented group . Similarly , there was no difference in the rate of fall between serum aspartate transaminase ( AST ) concentration in the two groups : the placebo group falling by a mean of 68.9 % ( + /- 35.2 ) and the antioxidant supplemented group falling by 70.1 % ( + /- 10.0 ) ( P = 0.41 , NS ) over the first 7 days of hospitalization . Alcoholics had low serum concentrations of vitamin E compared with controls ( 15.6 mg/l + /- 6.2 S.D. ) which rose more in the supplemented group over the period of a week ( 7.7 mg/l + /- 4.4 to 21.6 mg/l + /- 5.1 ) ( a mean rise of 180.5 % ) compared with the placebo group ( 8.6 mg/l + /- 6.8 to 9.6 mg/l + /- 5.7)--a mean rise of 11.6 % ( P = 0.006 ) . ( ABSTRACT TRUNCATED AT 250 WORDS Thirty abstinent male alcoholics with sexual dysfunction  were r and omized to treatment with 3 mg RE ( 10,000 IU ) vitamin A or placebo daily for 4 mo . Age , drinking history , period of abstinence before enrollment , and base-line laboratory indices were comparable in both groups at entry . Of the 15 subjects given placebo  , 13 had a partial or full recovery of sexual functioning . By contrast , of those given vitamin A , 10 had a partial response . There were no complete responders . Six subjects ( 1 placebo , 5 vitamin A ) who developed liver abnormalities during treatment underwent liver biopsies ; five had fibrosis or cirrhosis . A significant decrease in luteinizing hormone was noted in the group given vitamin A compared with the placebo-treated group . Thus vitamin A therapy did not improve  sexual functioning in male alcoholics and may have been associated with toxicity Patients with chronic hepatitis C virus ( HCV ) infection often develop liver cirrhosis and hepatocellular carcinoma ( HCC ) . The purpose of this study was to test the chemopreventive effect of alpha-tocopherol on hepatocarcinogenesis in patients with liver cirrhosis and a history of HCV infection . Eighty-three patients with liver cirrhosis and with positive history of HCV infection were divided at r and om into two groups . Forty-four patients were treated with alpha-tocopherol ( Vit E group ) while the other 39 were followed as controls . The clinical background ( gender , age , and laboratory data ) was similar in the two groups . Serum levels of alpha-tocopherol , albumin , alanine aminotransferase ( ALT ) , and total cholesterol and platelet count were measured serially over a period of five years . The mean serum concentration of alpha-tocopherol was low in both groups at entry and was significantly higher in the Vit E group than in the control group one month after treatment . Platelet count , serum albumin , ALT , and total cholesterol were not different between the two groups during the five-year period . Cumulative tumor-free survival and cumulative survival rate tended to be higher in the Vit E group than in controls , albeit statistically insignificant . The serum level of alpha-tocopherol was low in patients with liver cirrhosis and positive for HCV . Although the administration of alpha-tocopherol normalized the level one month later , it could neither improve liver function , suppress hepatocarcinogenesis , nor improve cumulative survival . Patients treated with alpha-tocopherol tended to live longer without development of HCC but the difference was not statistically significant Background Clinical evidence continues to exp and and is increasingly difficult to overview . We aim ed at conceptualizing a visual assessment tool , i.e. , a matrix for overviewing studies and their data in order to assess the clinical evidence at a glance . Methods A four-step matrix was constructed using the three dimensions of systematic error , r and om error , and design error . Matrix step I ranks the identified studies according to the dimensions of systematic errors and r and om errors . Matrix step II orders the studies according to the design errors . Matrix step III assesses the three dimensions of errors in studies . Matrix step IV assesses the size and direction of the intervention effect . Results The application of this four-step matrix is illustrated with two examples : peri-operative beta-blockade initialized in relation to surgery versus placebo for major non-cardiac surgery , and antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation .  When clinical evidence is deemed both internally and externally valid , the size of the intervention effect is to be assessed . Conclusion The error matrix provides an overview of the validity of the available evidence at a glance , and may assist in deciding which interventions to use in clinical practice Purpose . Ascorbic acid was administered to patients with chronic hepatitis C to eluci date the mechanism of onset of retinopathy during interferon ( IFN ) therapy , and its prevention . Methods . The subjects were 62 patients with chronic hepatitis C who had been admitted to our hospital . For the IFN therapy , 6 MIU of natural IFN-α or 10 MIU of recombinant human IFN-α 2b was administered every day for the first 2 weeks , followed by administration three times a week for 22 weeks . The patients were r and omly assigned to a group receiving 600 mg/day of ascorbic acid or a group not receiving ascorbic acid ( control group ) . The optic fundi were examined by ophthalmologists before the IFN therapy began and subsequently at weeks 2 and 4 and then every 4 weeks during the IFN therapy . Results . Retinopathy was found in 9 of the 31 patients ( 29 % ) in the ascorbic acid-treated group and in 11 of the 31 patients ( 35 % ) in the control group . The cumulative incidence of hemorrhage in the ascorbic acid-treated group was lower than that in the control group during the IFN therapy , but the difference between the two groups was not significant ( P = 0.186 ) . The cumulative incidence of cotton-wool spots in the ascorbic acid-treated group was almost same as that in the control group during the IFN therapy . The median platelet counts before the therapy was begun were 11.8 × 104/mm2 in the group with hemorrhage and 16.6 × 104/mm2 in the group without , and the lowest platelet counts during IFN therapy were 7.3 × 104/mm3 in the group with hemorrhage and 9.5 × 104/mm3 in the group without , indicating significantly lower values in the group with hemorrhage ( P = 0.018 and P = 0.020 , respectively ) . The lowest platelet counts during IFN therapy were 7.4 × 104/mm3 in the group with cotton-wool spots and 9.7 × 104/mm3 in the group without , indicating a significantly lower value in the group with cotton-wool spots ( P = 0.036 ) . Conclusions . Ascorbic acid was not considered to be useful for the prevention of the retinopathy associated with IFN therapy in patients with chronic hepatitis BACKGROUND AND AIMS Liver surgery usually involves ischemia and reperfusion ( I/R ) which results in oxidative stress and cell damage . The administration of antioxidants should diminish or prevent this damage . The purpose of this study was to investigate the effect of the antioxidant vitamin E on I/R injury . METHODS We carried out a placebo-controlled double-blind study on 68 patients undergoing elective , tumor-related , partial liver resection . 47 patients were qualified for the per protocol population based evaluation . The patients were r and omly assigned to two groups . The day before surgery one group received three infusions containing vitamin E ( 600 IU=540 mg vitamin E emulsion ) . The other group received three infusions of placebo . RESULTS Length of stay in the intensive care unit ( ICU ) was significantly shorter in the verum group than in the placebo group ( P<0.05 ) . There were signs of improvement for AUC AST ( P<0.05 ) , ALT and GLDH in the verum group after surgery . Serum vitamin E concentration increased after administration of vitamin E infusion and declined in both treatment groups after surgery ( P<0.01 ) . In the verum group vitamin E deficiency was prevented while vitamin E concentration remained low in the placebo group ( P<0.01 ) . CONCLUSIONS The findings from this study indicate that preoperative administration of vitamin E is safe and that this treatment may have beneficial effects by reducing the impact of I/R injury in liver surgery The effects of two forms of antioxidative co-therapy were analyzed in 24 interferon-alpha (IFN)-naive patients with chronic hepatitis C who were r and omized to either receive IFN monotherapy ( 3 x 4.5 million units IFN-alpha 2a per week ) , ( group A ) , or IFN and N-acetylcysteine ( N-acetylcysteine ( NAC ) 1.800 mg/day ) plus sodium selenite ( 400 microg/day ) supplementation ( group B ) , or treatment as in group B plus vitamin E ( 544 IU/day ) ( group C ) , over 24 weeks . Changes in histology , normalization of ALT , reduction of viral RNA , serum levels of glutathione , selenium , vitamin E , erythrocyte glutathione peroxidase , trolox equivalent antioxidative capacity ( TEAC ) , thiobarbituric acid reactive substances ( TBARS ) and protein carbonyl groups were measured . Low baseline TEAC and elevated TBARS indicated increased oxidative stress before therapy , which was not affected by antioxidant supplementation . At the end of treatment complete responses were found in 3/8 , 2/8 and 6/8 patients in groups A , B and C , respectively , but liver histology had not significantly improved . Vitamin E treated patients had a 2.4 greater chance ( 95 % CI : 1.05 - 5.5 ) of obtaining a complete response and had significantly greater reduction in viral load ( P = 0.028 ) than patients without vitamin E.  Relapses , i.e. re-appearance of detectable hepatitis C virus ( HCV ) RNA and /or re-elevation of ALT-activity occurred in 7 out of the 11 responders within 6 months after termination of therapy ( group A : 2/3 , group B : 1/2 and group C : 4/6 ) . Thus , no overall beneficial effect of antioxidant/IFN therapy was detected . However , the apparent trend towards a more favorable outcome with vitamin E supplementation warrants to further study this substance as an adjuvant to IFN therapy in chronic hepatitis OBJECTIVES To analyze sources search ed in Cochrane review s , to determine the proportion of trials included in review s that are indexed in major data bases , and to compare the quality of these trials with those from other sources . METHODS All new systematic review s in the Cochrane Library , Issue1 2001 , that were restricted to r and omized controlled trials ( RCTs ) or quasi- RCTs were selected . The sources search ed in the review s were recorded , and the trials included were checked to see whether they were indexed in four major data bases . Trials not indexed were checked to determine how they could be identified . The quality of trials found in major data bases was compared with those found from other sources . RESULTS The range in the number of data bases search ed per review ranged between one and twenty-seven . The proportion of the trials in the four data bases were Cochrane Controlled Trials Register = 78.5 % , MEDLINE = 68.8 % , Embase = 65.0 % , and Science/Social Sciences Citation Index = 60.7 % . Search ing another twenty-six data bases after Cochrane Controlled Trials Register ( CCTR ) , MEDLINE , and Embase only found 2.4 % additional trials . There was no significant difference between trials found in the CCTR , MEDLINE , and Embase compared with other trials , with respect to adequate allocation concealment or sample size . CONCLUSIONS There was a large variation between review s in the exhaustiveness of the literature search es . CCTR was the single best source of RCTs . Additional data base search ing retrieved only a small percentage of extra trials . Contacting authors and manufacturers to find unpublished trials appeared to be a more effective method of obtaining the additional better quality trials CONTEXT Selective reporting of outcomes within published studies based on the nature or direction of their results has been widely suspected , but direct evidence of such bias is currently limited to case reports . OBJECTIVE To study empirically the extent and nature of outcome reporting bias in a cohort of r and omized trials . DESIGN Cohort study using protocol s and published reports of r and omized trials approved by the Scientific-Ethical Committees for Copenhagen and Frederiksberg , Denmark , in 1994 - 1995 . The number and characteristics of reported and unreported trial outcomes were recorded from protocol s , journal articles , and a survey of trialists . An outcome was considered incompletely reported if insufficient data were presented in the published articles for meta- analysis . Odds ratios relating the completeness of outcome reporting to statistical significance were calculated for each trial and then pooled to provide an overall estimate of bias . Protocol s and published articles were also compared to identify discrepancies in primary outcomes . MAIN OUTCOME MEASURES Completeness of reporting of efficacy and harm outcomes and of statistically significant vs nonsignificant outcomes ; consistency between primary outcomes defined in the most recent protocol s and those defined in published articles . RESULTS One hundred two trials with 122 published journal articles and 3736 outcomes were identified . Overall , 50 % of efficacy and 65 % of harm outcomes per trial were incompletely reported . Statistically significant outcomes had a higher odds of being fully reported compared with nonsignificant outcomes for both efficacy ( pooled odds ratio , 2.4 ; 95 % confidence interval [ CI ] , 1.4 - 4.0 ) and harm ( pooled odds ratio , 4.7 ; 95 % CI , 1.8 - 12.0 ) data . In comparing published articles with protocol s , 62 % of trials had at least 1 primary outcome that was changed , introduced , or omitted . Eighty-six percent of survey responders ( 42/49 ) denied the existence of unreported outcomes despite clear evidence to the contrary . CONCLUSIONS The reporting of trial outcomes is not only frequently incomplete but also biased and inconsistent with protocol s. Published articles , as well as review s that incorporate them , may therefore be unreliable and overestimate the benefits of an intervention . To ensure transparency , planned trials should be registered and protocol s should be made publicly available prior to trial completion High rates of  hepatitis B virus ( HBV ) infection  and  primary liver cancer ( PLC )  are present in Qidong county . Epidemiological surveys demonstrated an inverse association between selenium ( Se ) level and regional cancer incidence , as well as HBV infection . Four-year animal studies showed that dietary supplement of Se reduced the HBV infection by 77.2 % and liver precancerous lesion by 75.8 % of ducks , caused by exposure to natural environmental etiologic factors . An intervention trial was undertaken among the general population of 130,471 . Individuals in five townships were involved for observation of the preventive effect of Se . The 8-yr follow-up data showed reduced PLC incidence by 35.1 % in selenized table salt supplemented vs the nonsupplemented population . On withdrawal of Se from the treated group , PLC incidence rate began to increase . However , the inhibitory response to HBV was sustained during the 3-yr cessation of treatment . The clinical study among 226 Hepatitis B Surface Antigen (HBsAg)-positive persons provided either 200 μg of Se in the form of selenized yeast tablet or an identical placebo of yeast tablet daily for 4 yr showed that 7 of 113 subjects were diagnosed as having PLC in the placebo group , whereas no incidence of PLC was found in 113 subjects supplemented with Se . Again on cessation of treatment , PLC developed at a rate comparable to that in the control group , demonstrating that a continuous intake of Se is essential to sustain the chemopreventive effect Objective To assess the effect of antioxidant supplementation on hepatitis C viral load , transaminases and oxidative status . Methods We performed a r and omized , placebo-controlled , double-blind trial to assess the effect of antioxidant supplementation on serum alanine aminotransferase , plasma hepatitis C viral load as well as oxidative and antioxidant markers in patients with hepatitis C virus infection . The participants received a daily dose of ascorbic acid ( 500 mg ) , D-&agr;-tocopherol ( 945 IU ) and selenium ( 200 μg ) or placebo tablets for 6 months . Results Twenty-three patients were included . During supplementation , the antioxidant group had significantly higher levels of plasma ascorbic acid and & agr;-tocopherol  than the placebo group and the activity of erythrocyte glutathione peroxidase had significantly increased from baseline to month 6 . No differences were observed in serum alanine aminotransferase and log10-transformed plasma hepatitis C virus-RNA between the groups or changes from the baseline at any time . No consistent differences between groups or changes from the baseline with respect to erythrocyte activities of antioxidative enzymes ( glutathione reductase , superoxide dismutase and catalase ) or plasma levels of oxidative markers ( malondialdehyde and 2-amino-adipic semialdehyde ) were found . Conclusion Supplementation with vitamin C , E and selenium  increased the antioxidant status , but had no effects on alanine aminotransferase , viral load or oxidative markers BACKGROUND AND AIMS Interferon-alpha treatment has been the treatment of choice for chronic hepatitis with unpredictable results . Recently , Lamivudine has been licensed for use against HBV infection with good results . Unfortunately , recurrence of viremia after lamivudine withdrawal is common and prolonged treatment can induce the emergence of resistant mutant strains . It has been shown that vitamin E can increase the host immune response , and this may provide protection against infectious diseases . METHODS We evaluated vitamin E supplementation as therapy for chronic hepatitis B in a pilot study including 32 patients . Patients were r and omly allocated to receive vitamin E at the dose of 300 mg twice daily for 3 months ( 15 patients ) or no treatment ( 17 patients ) . They were seen monthly during the first 3 months and thereafter quarterly for additional 12 months . RESULTS The two groups were comparable at enrollment . At the end of the study period , alanine aminotransferase ( ALT ) normalization was observed in 7 ( 47 % ) patients in vitamin E group and only in 1 ( 6 % ) of the controls ( P=0.011 ) ; HBV-DNA negativization was observed in 8 ( 53 % ) patients in the vitamin E group as compared to 3 ( 18 % ) in the control group , respectively ( P=0.039 ) . A complete response ( normal ALT and negative HBV-DNA ) was obtained in 7 ( 47 % ) patients taking vitamin E and in none of the controls ( P=0.0019 ) . CONCLUSION Vitamin E supplementation might be effective in the treatment of chronic hepatitis Objective : To test the effect of a 21-day supplementation with moderate doses of antioxidant nutrients on biochemical indicators of vitamin , carotenoid and trace element levels in alcohol-dependent patients during a program of alcohol rehabilitation . Design : A r and omized double-blind trial was performed comparing two groups receiving daily either a combination of micronutrients ( beta-carotene : 6 mg , vitamin C : 120 mg , vitamin E : 30 mg , zinc : 20 mg , selenium : 100 μg ) or a placebo . Subjects : 106 alcohol-dependent patients 20 to 60 years of age without severe liver disease , hospitalized for a 21-day rehabilitation program . Measure of Outcome : Vitamin C , retinol , α-tocopherol , zeaxanthin/lutein , β-cryptoxanthin , lycopene , α- and β-carotene , zinc and selenium were measured in serum , initially and after supplementation . Results : ( 1 ) In the placebo group , after 21 days of rehabilitation , serum concentrations of vitamin C and all five carotenoids significantly increased , whereas retinol and α-tocopherol concentrations decreased ; zinc and selenium levels were unaffected . ( 2 ) At the end of the hospital stay , serum indicators were significantly improved in the supplement group as compared to the placebo group for vitamin C , α-tocopherol , β-carotene , zinc and selenium ; conversely , lycopene changes were higher in the placebo group than in supplement group . ( 3 ) Of the serum antioxidants measured at entrance , only vitamin C was significantly depleted in heavy smokers , and , after the supplementation period , vitamin C was efficiently repleted in this later group . Conclusion : Our results indicate that a short-term supplementation with physiological doses of antioxidant vitamins , carotenoids and trace elements during alcohol rehabilitation clearly improves micronutrient status indicators . Heavy smokers in particular seem to respond to vitamin C supplementation Methods for combining data from several studies exist and appear to be quite useful . None satisfactorily addresses the question of what studies should be combined . This issue is the most serious method ological limitation . Even studies with statistically significant interaction might still be combined if the effect were in the same direction . Thus , substantial scientific input is required as to what criteria must be met by each potential study . Much can be learned from combining or pooling data but it must be done cautiously . Pooling exercises do not replace well design ed prospect i ve clinical trials . Efforts for establishing basic design criteria to allow for multicentre and multicountry trials to be more easily combined might be useful . To comprehend the results of a r and omized , controlled trial ( RCT ) , readers must underst and its design , conduct , analysis , and interpretation . That goal can be achieved only through complete transparency from authors . Despite several decades of educational efforts , the reporting of RCTs needs improvement . Investigators and editors developed the original CONSORT ( Consoli date d St and ards of Reporting Trials ) statement to help authors improve reporting by using a checklist and flow diagram . The revised CONSORT statement presented in this paper incorporates new evidence and addresses some criticisms of the original statement . The checklist items pertain to the content of the Title , Abstract , Introduction , Methods , Results , and Discussion . The revised checklist includes 22 items selected because empirical evidence indicates that not reporting the information is associated with biased estimates of treatment effect or because the information is essential to judge the reliability or relevance of the findings . We intended the flow diagram to depict the passage of participants through an RCT . The revised flow diagram depicts information from four stages of trial ( enrollment , intervention allocation , follow-up , and analysis ) . The diagram explicitly includes the number of participants , for each intervention group , that are included in the primary data analysis . Inclusion of these numbers allows the reader to judge whether the authors have performed an intention-to-treat analysis . In sum , the CONSORT statement is intended to improve the reporting of an RCT , enabling readers to underst and a trial 's conduct and to assess the validity of its results OBJECTIVE Alcohol ingestion promotes lipoperoxidation and alters cellular antioxidant mechanisms . Alpha-tocopherol levels decrease in alcoholics as severity of liver damage increases . The aim of this protocol was to study the effects of a long-term oral 500 mg vitamin E daily supplementation in decompensated ambulatory alcoholic cirrhotics . PATIENTS AND METHODS 67 subjects were included in this double blind trial ; 33 patients received vitamin E and 34 patients received placebo tablets of identical appearance during 1 year . Each month , the patients were seen by a nurse practitioner who was in charge of detecting alcohol ingestion and checking adherence to treatment . Every 3 months , the patients underwent a medical examination , and blood sample s were taken for clinical laboratory analysis and serum vitamin E measurement . RESULTS Alpha-tocopherol levels were significantly lower in patients with more severe liver disease . This difference was not significant when vitamin E levels were corrected by cholesterol . Oral supplementation significantly increased serum vitamin E levels in the experimental group . Alcohol ingestion and hospitalization rates were similar in both groups . Life table analysis did not show significant differences in mortality between the two groups . DISCUSSION Vitamin E supplementation with adequate doses of an alpha-tocopheryl acetate formulation during 1 year did not influence hepatic laboratory parameters , mortality or hospitalization rates of decompensated alcoholic cirrhotics , although serum levels of the vitamin significantly increased Toxic liver diseases coincide with oxidative stress correlating positively with the seriousness of the course of disease . For the purpose of elucidating the pathogenic significance of an increased radical generation . 56 patients suffering from acute alcohol-toxic hepatitis of the clinical grade of seriousness B and C according to Child/Pugh were classified r and omly into antioxidant subgroups ( n = 31 ) and control groups (= 25 ) . The basis therapy being identical , the patients of the antioxidant group received additionally 600 mg of D-alpha tocopherol per day , 200 micrograms of selenium and 12 mg of zinc . Due to the supplementation of antioxidants there were quicker significant changes in the concentration of bilirubin , malondialdehyde and of ammonia in the serum . In comparison with the control group the length of stay in hospital could be reduced by 6 days . In the control group the mortality rates amounted to 40 % ( 10 of 25 ) , in the antioxidant group to 6.5 % ( 2 of 31 ) . The results confirm the pathogenic significance of oxidative stress in alcohol-toxic liver disease because a distinct improvement of prognosis could be achieved by using a low-cost adjuvant antioxidant supplementation OBJECTIVE : Nonalcoholic steatohepatitis ( NASH ) is a common cause of liver disease . Although usually indolent , this disease can progress to cirrhosis in some patients . There is currently no proven medical therapy for the treatment of NASH . The aim of our study was to evaluate the efficacy of combination α-tocopherol ( vitamin E ) and vitamin C in reducing histologic inflammation and fibrosis . METHODS : This was a prospect i ve , double-blind , r and omized , placebo-controlled trial with a total enrollment of 49 patients ; 45 patients completed the study . All patients were r and omized to receive either vitamins E and C ( 1000 IU and 1000 mg , respectively ) or placebo daily for 6 months , based on their initial histologic diagnosis of NASH . Additionally , all patients were given st and ard weight-loss counseling and encouraged to follow a low fat diet ( < 30 fat g/day ) . The pre- and posttreatment liver biopsies were review ed by a single pathologist , who was blinded to the patient 's medication . Biopsies were scored based on a modification of the scoring system published by Brunt et al. ( Am J Gastroenterol 1999;94:2467–74 ) . A score of 0–4 was possible for fibrosis , and a score of 0–6 was possible for inflammation and hepatocyte degeneration and necrosis . In addition , body mass index , glycohemoglobin , lipids , and liver enzymes were followed throughout the study . RESULTS : Forty-five patients completed 6 months of therapy without significant side effects  . Vitamin treatment result ed in a statistically significant improvement in fibrosis score ( p = 0.002 ) . No changes were noted in inflammation with treatment . CONCLUSIONS : Vitamin E and vitamin C , in the doses used in this study , were well tolerated and were effective in improving fibrosis scores in NASH patients . No improvement in necroinflammatory activity or ALT was seen with this combination of drug therapy . A larger , multicenter , longer-term trial with vitamin E and vitamin C seems to be warranted Summary of the Recommendations The U.S. Preventive Services Task Force ( USPSTF ) concludes that the evidence is insufficient to recommend for or against the use of supplements of vitamins A , C , or E ; multivitamins with folic acid ; or antioxidant combinations for the prevention of cancer or cardiovascular disease . This is a grade I recommendation . ( See Appendix Table 1 for a description of the USPSTF classification of recommendations . ) The USPSTF found poor evidence to determine whether supplementation with these vitamins reduces the risk for cardiovascular disease or cancer . ( See Appendix Table 2 for a description of the USPSTF classification of levels of evidence . ) The available evidence from r and omized trials is either inadequate or conflicting , and the influence of confounding variables on observed outcomes in observational studies can not be determined . As a result , the USPSTF could not determine the balance of benefits and harms of routine use of supplements of vitamins A , C , or E ; multivitamins with folic acid ; or antioxidant combinations for the prevention of cancer or cardiovascular disease . The USPSTF recommends against the use of beta-carotene supplements , either alone or in combination , for the prevention of cancer or cardiovascular disease . This is a grade D recommendation . The USPSTF found good evidence that -carotene supplementation provides no benefit in the prevention of cancer or cardiovascular disease in middle-aged and older adults . In two trials restricted to heavy smokers , -carotene supplementation was associated with higher incidence of lung cancer and higher all-cause mortality . The USPSTF concludes that -carotene supplements are unlikely to provide important benefits and might cause harm in some groups . Clinical Considerations The USPSTF did not review evidence regarding vitamin supplementation for patients with known or potential nutritional deficiencies , including pregnant and lactating women , children , elderly persons , and people with chronic illnesses .  Dietary supplements may be appropriate for people whose diet does not provide the recommended dietary intake of specific vitamins . Individuals may wish to consult a health care provider to discuss whether dietary supplements are appropriate . With the exception of vitamins for which there is compelling evidence of net harm ( for example , beta-carotene supplementation in smokers ) , there is little reason to discourage people from taking vitamin supplements . Patients should be reminded that taking vitamins does not replace the need to eat a healthy diet . All patients should receive information about the benefits of a diet high in fruits and vegetables , as well as information on other foods and nutrients that should be emphasized or avoided in their diet ( see the 2002 USPSTF recommendations on counseling to promote a healthy diet [ 1 ] ) . Patients who choose to take vitamins  should be encouraged to adhere to the dosages recommended in the Dietary Reference Intakes of the Institute of Medicine . Some vitamins , such as A and D , may be harmful in higher doses ; therefore , doses greatly exceeding the Recommended Dietary Allowance or Adequate Intake should be taken with care while considering whether potential harms outweigh potential benefits . Vitamins and minerals sold in the United States are classified as dietary supplements , and there is a degree of quality control over content if they have a U.S. Pharmacopeia seal ( 2 ) . Nevertheless , imprecision in the content and concentration of ingredients could pose a theoretical risk not reflected in clinical trials using calibrated compounds . The adverse effects of beta-carotene on smokers have been observed primarily in those taking large supplemental doses . There is no evidence to suggest that beta-carotene is harmful to smokers at levels occurring naturally in foods . The USPSTF did not review evidence supporting folic acid supplementation among pregnant women to reduce neural tube defects . In 1996 , the USPSTF recommended folic acid for all women who are planning , or capable of , pregnancy ( see the 1996 USPSTF chapter on screening for neural tube defects [ 3 ] ) . Clinicians and patients should discuss the possible need for vitamin supplementation when taking certain medications ( for example , folic acid supplementation for patients taking methotrexate ) . Scientific Evidence The USPSTF review s ( 4 - 6 ) focused on the quality of the evidence regarding the effect of routine supplementation with certain vitamins on primary prevention of cancer and cardiovascular disease . These review s were undertaken because of the growing epidemiologic evidence that dietary factors may play a role in the etiology of these diseases ( 7 - 9 ) . The review s focused on prospect i ve trials of vitamin supplementation and observational studies of associations between the use of specific supplements and the risk for cancer or cardiovascular disease . The value of vitamins naturally occurring in food , the use of vitamin supplements for the prevention of other conditions ( for example , neural tube defects ) , and the use of vitamin supplements for the secondary prevention of complications in patients with existing disease were outside the scope of these review s. Vitamin A No prospect i ve trials have examined the effect of vitamin A supplements alone on the risk for cancer . Observational studies provide no evidence that such supplements prevent cancer in men . In women , observational studies have reported a statistically significant inverse association between use of vitamin A supplements and risk for colon and breast cancer ( 10 , 11 ) . Despite efforts to adjust for confounding variables , the observational , nonr and om design of these studies makes it difficult to assess the extent to which the reduced cancer risk is attributable to vitamin A or to other characteristics of women who take vitamin A supplements .  No evidence from prospect i ve trials is available regarding the benefits of vitamin A alone in preventing cardiovascular disease . One good- quality cohort study found no effect of vitamin A supplementation in reducing cardiovascular disease mortality ( 12 ) . Vitamin C No primary prevention trial of the effect of vitamin C supplementation alone on cancer or cardiovascular disease has been reported . Observational studies have generally shown no statistically significant associations between use of vitamin C supplements and risk for cancer of the breast , prostate , colon , or lung ( 12 - 14 ) . The observational cohort studies examining the effects of vitamin C on cardiovascular disease have produced inconsistent results ( 12 , 15 , 16 ) . Vitamin E Only a few trials have examined the effects of vitamin E on the primary prevention of cancer or cardiovascular disease . A r and omized , controlled trial ( RCT ) involving Finnish male smokers found that vitamin E supplementation is not protective against lung cancer but may have a beneficial impact on prostate cancer ( 14 ) . Because prostate cancer was not a primary end point of the trial and the trial had other limitations , further evidence is needed to confirm this finding . Observational studies have shown no statistically significant association between use of vitamin E supplements and risk for prostate , lung , or breast cancer ( 5 ) . One study suggested that vitamin E protects against colon cancer , but the influence of confounding variables can not be fully excluded ( 17 ) . Among primary prevention trials , two good- quality trials ( 14 , 18 ) and one fair- quality trial ( 19 ) found no statistically significant benefit of vitamin E supplementation in preventing cardiovascular disease ( 20 ) . Only one of seven trials of vitamin E supplementation for secondary prevention demonstrated a statistically significant reduction in cardiac events ( 4 ) . Some prospect i ve cohort studies have suggested a significant benefit , but the results are mixed and the influence of confounding variables can not be excluded ( 4 ) . -Carotene A consistent body of evidence from clinical trials suggests that beta-carotene supplementation does not decrease the risk for lung , prostate , colon , breast , or nonmelanoma skin cancer ( 14 , 21 - 25 ) . -Carotene supplements were associated with an increased risk for lung cancer among smokers , especially heavy smokers , in two RCTs ( 14 , 25 ) . Results from four RCTs demonstrated no reduced risk for cardiovascular events or death after beta-carotene supplementation ( 14 , 21 , 22 , 26 - 28 ) . Antioxidant Vitamin Combinations Studies of the effects of antioxidant vitamin combinations to prevent cancer have yielded mixed results . A recent RCT reported no statistically significant effect of daily supplementation with a combination of antioxidants : vitamin E , vitamin C , and beta-carotene ( 29 ) . Some studies have suggested an adverse effect of antioxidant combinations on cancer , but the results may have been confounded by the inclusion of beta-carotene ( 5 ) . Some observational studies of antioxidant vitamin combinations have suggested a benefit in preventing cardiovascular disease ( 13 , 30 , 31 ) , but other studies , including well- design ed RCTs , have shown no benefit ( 29 , 32 , 33 ) . One secondary prevention trial showed an increase in all-cause mortality among women taking antioxidant supplements  ( 34 ) . Multiple Vitamin Combinations The incremental benefit of taking supplemental doses of folic acid and B vitamins has been examined by comparing the outcomes of observational studies while controlling for the total intake of antioxidant vitamin supplements ( 35 ) . In these analyses , folic acid supplementation was associated with significantly decreased risk for colon cancer , but the protective effect requires confirmation in prospect i ve trials . There is conflicting evidence regarding the use of multivitamins and the risk for cardiovascular disease . Among cohort studies , one good- quality study reported a statistically significant reduction in coronary events ( 36 ) , two good- quality studies reported no statistically significant effect on mortality ( 16 , 37 ) , and one Background : We have previously reported , in an uncontrolled trial , an improvement in fatigue scores in patients with primary biliary cirrhosis given oral antioxidant supplementation . We now present data from a controlled trial OBJECTIVES : Metformin proved useful in the treatment of nonalcoholic fatty liver disease ( NAFLD ) , but its superiority over nutritional treatment and antioxidants has never been demonstrated . We aim ed to compare the usefulness of metformin versus prescriptive diet or vitamin E. METHODS : In an open label , r and omized trial , nondiabetic NAFLD patients were given metformin ( 2 g/day ; n = 55 ) for 12 months . The control cases were given either vitamin E ( 800 IU/day ; n = 28 ) or were treated by a prescriptive , weight-reducing diet ( n = 27 ) . Outcome measures were liver enzymes , insulin resistance ( homeostasis model assessment ) , parameters of the metabolic syndrome , and histology . RESULTS : Aminotransferase levels improved in all groups , in association with weight loss . The effects in the metformin arm were larger ( p < 0.0001 ) , and alanine aminotransferase normalized in 56 % of cases ( odds ratio ( OR ) versus . controls , 3.11 ; 95 % confidence interval ( CI ) , 1.56–6.20 ; p = 0.0013 ) . In multivariate analysis , metformin treatment was associated with higher rates of aminotransferase normalization , after correction for age , gender , basal aminotransferases , and change in body mass index ( OR , 5.98 ; 95 % CI , 2.05–17.45 ) . Differences were maintained when the two control groups were separately analyzed . The distribution of positive criteria for the metabolic syndrome was reduced only in the metformin arm ( p = 0.001 , signed rank test ) . A control biopsy in 17  metformin-treated cases ( 14 nonresponders ) showed a significant decrease in liver fat ( p = 0.0004 ) , necroinflammation , and fibrosis ( p = 0.012 for both ) . No side effects were observed during metformin treatment . CONCLUSIONS : Metformin treatment is better than a prescriptive diet or vitamin E in the therapy of NAFLD patients receiving nutritional counseling . Limited histological data support an association between improved aminotransferases and biopsy findings , which require confirmation in a double-blind trial with appropriate statistical power based on liver histology Background :  Ribavirin  is associated with haemolytic anaemia . Antioxidants have been reported to decrease severity of this anaemia OBJECTIVE After non-response to the initial course of therapy , retreatment with alpha-interferon is not effective . The aim of this study was to ascertain whether the administration of N-acetyl cysteine and vitamin E could increase the response rate to retreatment with alpha-interferon . DESIGN Prospect i ve , multicentre clinical trial . SETTING Twelve hospitals in Lombardy , Italy . PARTICIPANTS 120 consecutive patients affected by biopsy-proven chronic hepatitis C who had been non-responders to a previous course of alpha-interferon  , administered at the dosage of 3 - 6 million units ( MU ) three times a week ( tiw ) for 6 months . INTERVENTIONS The patients were r and omly assigned to one of two groups of treatment : group A , natural interferon-alphaN3 , 6 or 9 MU tiw , when the body weight was < 60 kg or > or = 60 kg , respectively ; group B , the same dosage of natural interferon-alphaN3 in association with oral administration of N-acetyl cysteine 1200 mg/day and vitamin E 600 mg/day . The period of treatment was 6 months in both groups . RESULTS Neither end-therapy biochemical response nor sustained biochemical response rates were improved by the combination treatment , and in no case was clearance of the virus from serum observed . CONCLUSIONS In this r and omized study carried out on 120 patients with chronic hepatitis C not responsive to alpha-interferon , oral supplementation with N-acetyl cysteine and vitamin E did not improve the poor efficacy of retreatment with alpha-interferon alone BACKGROUND / AIMS It has been shown that alcohol impairs erythrocyte ( red blood cell ) membrane fluidity and lipid composition . The aim of this study was to test the effect of a novel acid-resistant antioxidant on the hemorrheology in alcoholics . METHODOLOGY Thirty alcoholics ( 25 males , 5 females ; mean age : 42 years ; range : 31 - 54 ; 150 g ethanol/day for 3 - 5 years ) were enrolled into the study . Patients were r and omly and double-blindly allocated into 2 groups which were given , for a 2 week period , 18 g/day of Bionormalizer ( obtained from biofermentation of carica papaya , pennisetum purpureum , sechium edule , Osato Res . Foundation , Gifu , Japan ) dissolved in 5 mL of water at bedtime and 3 hours prior to examination . Placebo consisted of flavored sugar . Healthy teetotalers  served as control . On the examination day , blood sample s were taken for testing : routine tests , plasma glutathione , ascorbic acid , selenium , plasma lipid hydroperoxides and alpha-tocopherol . Erythrocytes were separated and tested for red blood cell malonyldialdehyde and glutathione content . The hemorheological studies were as follows : blood and plasma viscosity , whole blood filterability , red blood cell membrane fluidity by electron spin resonance , red blood cell aggregation index by photometric rheoscopy and red blood cell deformability by ektacytometry . RESULTS As compared to healthy controls , alcoholics on placebo treatment showed no change of plasma viscosity but a significantly higher red blood cell malonyldialdehyde , blood viscosity ( P < 0.05 ) and lower plasma glutathione , whole blood filterability and red blood cell fluidity ( P < 0.01 ) . No relationship appeared between biochemical tests and red blood cell membrane fluidity . Bionormalizer group showed a significant recovery to control values of either blood viscosity and whole blood filterability ( P < 0.01 ) and a partial , although significant , improvement of red blood cell membrane fluidity , red blood cell malonyldialdehyde and plasma glutathione ( P < 0.05 ) . As compared to healthy control , red blood cell aggregation decreased in alcoholics ( P < 0.05 ) and was not affected by Bionormalizer . However , Bionormalizer significantly improved the reduced red blood cell deformability ( P < 0.05 vs. alcoholics ) and this parameter correlated with red blood cell malonyldialdehyde ( r : 0.62 . P < 0.05 ) . CONCLUSIONS These preliminary data suggest that an effective antioxidant supplementation is able to improve the hemorrheology in alcoholics either by directly affecting the ethanol-related lipoperoxidation and xanthine oxidase system activation and /or by modifying red blood cell membrane characteristics AIM To assess the safety and efficacy of antioxidant therapy for patients with chronic hepatitis C virus ( HCV ) infection . METHODS One hundred chronic HCV infection patients failed in interferon treatment were enrolled and r and omly assigned to receive combined intravenous and oral antioxidants or placebo , or oral treatment alone . Primary end points were liver enzymes , HCV-RNA levels and histology . RESULTS Combined oral and intravenous antioxidant therapy was associated with a significant decline in ALT levels in 52 % of patients who received antioxidant therapy vs 20 % of patients who received placebo ( P = 0.05 ) . Histology activity index ( HAI ) score at the end of treatment was reduced in 48 % of patients who received antioxidant therapy vs 26 % of patients who received placebo ( P = 0.21 ) . HCV-RNA levels decreased by 1-log or more in 28 % of patients who received antioxidant therapy vs 12 % who received placebo ( P = NS ) . In part II of the trial , oral administration of antioxidants was not associated with significant alterations in any of the end points . CONCLUSION Antioxidant therapy has a mild beneficial effect on the inflammatory response of chronic HCV infection patients who are non-responders to interferon .  Combined antiviral and antioxidant therapy may be beneficial for these patients Patients with cirrhosis show intrahepatic endothelial dysfunction , characterized by an impaired flow-dependent vasorelaxation . This alteration is responsible for the marked postpr and ial increase in portal pressure and is attributed to an insufficient release of nitric oxide ( NO ) . Ascorbic acid reverts endothelial dysfunction in other vascular disorders , via the increase of NO bioavailability through the neutralization of superoxide anions , thus preventing the scavenging of NO by superoxide . This study examined whether acute ascorbic acid administration might improve endothelial dysfunction in cirrhosis . Thirty-seven portal hypertensive patients with cirrhosis had measurements of hepatic and systemic hemodynamics , ascorbic acid , and malondialdehyde ( MDA ) .  Patients were r and omly allocated to receive ascorbic acid ( 3 g , intravenously , n = 15 ) or placebo ( n = 12 ) followed by a liquid meal . A third group received ascorbic acid followed by a sham meal ( n = 10 ) . Measurements were repeated after 30 minutes ( hepatic venous pressure gradient at 15 and 30 minutes ) . Patients with cirrhosis had significantly lower ascorbic acid levels and higher MDA than healthy controls . Ascorbic acid significantly reduced MDA levels and markedly attenuated the postpr and ial increase in the hepatic venous pressure gradient ( 4 % + /- 7 % vs. 18 % + /- 10 % in placebo at 30 minutes , P < .001 ) . Ascorbic acid followed by sham meal did not modify hepatic or systemic hemodynamics . In conclusion , patients with cirrhosis exhibited intrahepatic endothelial dysfunction , associated with decreased levels of ascorbic acid and increased levels of MDA . Ascorbic acid improved intrahepatic endothelial dysfunction , blunting the postpr and ial increase in portal pressure . These results encourage the performance of further studies testing antioxidants as adjunctive therapy in the treatment of portal hypertension Background : The pathogenesis of chronic hepatitis C virus ( HCV ) infection is associated with a defective host antiviral immune response and intrahepatic oxidative stress . Oxidative stress and lipid peroxidation play major roles in the fatty liver accumulation ( steatosis ) that leads to necro-inflammation and necrosis of hepatic cells . Previous trials suggested that antioxidative therapy may have a beneficial effect on patients with chronic HCV infection . Aims : To determine the safety and efficacy of treatment of chronic HCV patients via a combination of antioxidants . Methods : Fifty chronic HCV patients were treated orally on a daily basis for 20 weeks with seven antioxidative oral preparations ( glycyrrhizin , schis and ra , silymarin , ascorbic acid , lipoic acid , L-glutathione , and alpha-tocopherol ) , along with four different intravenous preparations ( glycyrrhizin , ascorbic acid , L-glutathione , B-complex ) twice weekly for the first 10 weeks , and followed up for an additional 20 weeks . Patients were monitored for HCV-RNA levels , liver enzymes , and liver histology . Assessment of quality of life was performed using the SF-36 question naire . Results : In one of the tested parameters ( eg , liver enzymes , HCV RNA levels , or liver biopsy score ) , a combination of antioxidants induced a favorable response in 48 % of the patients ( 24 ) . Normalization of liver enzymes occurred in 44 % of patients who had elevated pretreatment ALT levels ( 15 of 34 ) . ALT levels remained normal throughout follow-up period in 72.7 % ( 8 of 11 ) . A decrease in viral load ( one log or more ) was observed in 25 % of the patients ( 12 ) . Histologic improvement ( 2-point reduction in the HAI score ) was noted in 36.1 % of the patients . The SF-36 score improved in 26 of 45 patients throughout the course of the trial ( 58 % of the patients ) . Treatment was well tolerated by all patients . No major adverse reactions were noted . Conclusions : These data suggest that multi antioxidative treatment in chronic HCV patients is well tolerated and may have a beneficial effect on necro-inflammatory variables . A combination of antiviral and antioxidative therapies may enhance the overall response rate of these patients The relationship among impaired selenium status , lipid peroxidation , and liver function was examined in 19 hospitalized patients with severe alcoholic cirrhosis .  Plasma selenium was found to be significantly lower ( mean±SD : 54±13 μg/L ) than in healthy controls ( 83±11 μg/L ) and plasma malondialdehyde , assessed as thiobarbituric acid reactants , which reflects lipid peroxidation , was increased ( 2.0±1.2 μmol/L vs < 1.2 μmol/L in controls ) . The mean14C aminopyrine breath test , an indicator of liver function , was lower than normal ( 2.7±1.9 vs 6.3±0.9 % in controls ) and found to be significantly correlated with plasma selenium ( r=0.59,p<0.05 ) . A prospect i ve , r and omized selenium supplementation trial was conducted in a group of 16 patients who received either daily 100 μg selenium as enriched yeast during 4 mo or a placebo . Among the 10 patients who completed the study , plasma selenium significantly increased in the supplemented group ( n=4 ; before : 58±10 μg/L , and after 101±12 μg/L , p<0.01 ) contrary to the placebo group ( n=6 , before : 47±10 μg/L , after : 57±9 μg/L , n.s.),14C aminopyrine breath test improved in three out of four selenium-supplemented patients and in three out of six placebo patients , but the small number of patients did not allow statistical evaluation . These results demonstrate that low selenium status in alcoholic cirrhosis is correlated to liver function and could be improved by supplementation BACKGROUND & AIMS Nonalcoholic steatohepatitis ( NASH ) is a frequent liver disease that can progress to cirrhosis and for which there is no recognized therapy . UDCA and vitamin E have been considered separately as therapeutic options and have not been shown to be effective . This study tested their combination . METHODS Patients with elevated aminotransferase levels and drinking less than 40 g alcohol/week with biopsy-proven NASH were r and omly assigned to receive UDCA 12 - 15 mg.kg-1.day-1 with vitamin E 400 IU twice a day ( UDCA/Vit E ) , UDCA with placebo ( UDCA/P ) , or placebo/placebo ( P/P ) . After 2 years , they underwent a second liver biopsy . Biopsy specimens were collected , blinded , and scored by a single liver pathologist . RESULTS Forty eight patients were included , 15 in the UDCA/Vit E group , 18 in the UDCA/P group , and 15 in the P/P group ; 8 patients dropped out , none because of side effects .  Baseline parameters were not significantly different between the 3 groups . Body mass index remained unchanged during the study . Serum aspartate aminotransferase ( AST ) and alanine aminotransferase ( ALT ) levels diminished significantly in the UDCA/Vit E group . Neither the AST nor the ALT levels improved in the P/P group and only the ALT levels in the UDCA/P group . Histologically , the activity index was unchanged at the end of the study in the P/P and UDCA/P groups , but it was significantly better in the UDCA/Vit E group , mostly as a result of regression of steatosis . CONCLUSIONS Two years of treatment with UDCA in combination with vitamin E improved laboratory values and hepatic steatosis of patients with NASH . Larger trials are warranted A new high performance liquid chromatographic method has been used to measure erythrocyte levels of the physiologically active form of thiamin , thiamin diphosphate ( ETDP ) , in 25 alcoholics admitted to hospital for detoxification and rehabilitation . Measurements were made before , during and after multivitamin supplementation , either orally or parenterally , on a controlled basis . Before treatment , only one case of thiamin deficiency was detected . Within 24 hr of receiving 250 mg of thiamin both treated groups showed an increase in their mean ETDP levels , though only that of the parenterally treated group was significantly higher ( P less than 0.05 ) than the pre-treatment mean . However , after 250 mg thiamin daily for 5 days , both treated groups showed a significant ( P less than 0.05 ) and almost identical increase in their mean ETDP levels ( 90 nmol/l . and 91 nmol/l . for the oral and parenteral routes respectively ) . The results suggest that except for alcoholics requiring thiamin urgently , for whom the parenteral route is demonstrably quicker at raising tissue levels , oral supplementation achieves the same result as parenteral BACKGROUND & AIMS Oxidative stress mediates activation and stimulates collagen production of cultured hepatic stellate ( Ito ) cells . The aim of this study was to assess whether oxidative stress contributes to hepatic fibrogenesis in chronic hepatitis C. METHODS In liver biopsy specimens of patients with chronic hepatitis C , the following fibrogenesis cascade was analyzed : ( 1 ) oxidative stress , determined by the presence of malondialdehyde protein adducts ; ( 2 ) activation of stellate cells as indicated by their expression of alpha-smooth muscle actin ; ( 3 ) stimulation of c-myb expression in stellate cells , a critical step in the activation of these cells ; and ( 4 ) induction of collagen gene expression as detected by in situ hybridization . RESULTS Treatment with d-alpha-tocopherol ( 1200 IU/day for 8 weeks ) in 6 of these patients , who were refractory to interferon therapy , prevented the fibrogenesis cascade observed before antioxidant treatment . In addition , d-alpha-tocopherol treatment significantly decreased the carbonyl modifications of plasma proteins , a sensitive index of oxidative stress . However , 8 weeks of d-alpha-tocopherol treatment did not significantly affect serum alanine aminotransferase levels , hepatitis C virus titers , or histological degree of hepatocellular inflammation or fibrosis . CONCLUSIONS These data suggest that enhanced oxidative stress initiates a fibrogenesis cascade in the liver of patients with chronic hepatitis There are few data evaluating plasma and /or peripheral blood monocyte cytokine concentrations/production or attempts to manipulate proinflammatory cytokines in nonalcoholic steatohepatitis ( NASH ) . A pilot project in a general clinical research center evaluated the effects of a step 1 American Heart Association diet plus aerobic exercise with or without 800 IU of vitamin E daily on cytokine profiles and liver enzyme levels in 16 patients with biopsy-proven NASH .  Biochemical assessment of liver function , lipid profiles , and body mass index significantly improved during the first 6 weeks of therapy and remained stable during the following 6 weeks . Plasma hyaluronic acid ( HA ) concentrations decreased in parallel with weight loss . Plasma tumor necrosis factor ( TNF ) concentrations were significantly elevated in patients with NASH and similar to patients with stable alcoholic cirrhosis but not as elevated as in patients with acute alcoholic steatohepatitis ( AH ) . Although plasma TNF , interleukin 8 ( IL-8 ) , and IL-6 concentrations were all significantly elevated compared with control values , only plasma IL-6 levels significantly decreased with therapy . Peripheral blood monocyte TNF , IL-8 , and IL-6 production was significantly elevated in patients with NASH but did not significantly decrease . Independent effects of vitamin E were not observed in this small sample . In conclusion , patients with NASH have dysregulated cytokine metabolism similar to , but less pronounced than abnormalities documented in AH . Cytokine values generally did not decrease significantly with weight loss with or without vitamin E over the duration of the study . Lifestyle modifications ( low-fat diet and exercise ) were associated with improvement in liver enzymes , cholesterol , and plasma HA levels in patients with NASH , whereas the level of vitamin E supplementation used in this short-term pilot study provided no apparent added benefit BACKGROUND / AIMS Oxidative stress is putatively involved in the pathogenesis of alcohol-induced liver injury . This trial was devised to determine whether antioxidant therapy , alone or as an adjunct to corticosteroids , improved survival in patients with acute alcoholic hepatitis . METHODS Patients with a severe alcoholic hepatitis were stratified by sex and steroid use , and then r and omized . The active group received N-acetylcysteine for one week , and vitamins A-E , biotin , selenium , zinc , manganese , copper , magnesium , folic acid and Coenzyme Q daily for 6 months . The trial was double blinded and placebo controlled . The primary end-point was mortality within 6 months . RESULTS Thirty-six ( 20 male , 16 female ; mean discriminant function ( DF ) 86.6 ) received active drug , and 34 ( 18 male , 16 female ; mean DF 76.4 ) received placebo .  180-day survival was not significantly different between patients receiving drug and placebo ( 52.8 % vs. 55.8 % , p=0.699 ) . This was not affected by stratification for steroid use or sex . The only predictors of survival in multivariate analysis were initial bilirubin ( p=0.017 ) , white cell count ( p=0.016 ) and age ( p=0.037 ) . Treatment allocation did not affect survival in multivariate analysis ( p=0.830 ) . CONCLUSIONS Antioxidant therapy , alone or in combination with corticosteroids , does not improve 6-month survival in severe alcoholic hepatitis AIM To investigate the efficacy of Viusid , a nutritional supplement , as an antioxidant and an immunomodulator in patients with chronic hepatitis C. METHODS Sixty patients with chronic hepatitis C who were non-responders to st and ard antiviral treatment were r and omly assigned to receive Viusid ( 3 sachets daily , n = 30 ) or placebo ( n = 30 ) for 24 wk . The primary outcome was the change in serum malondialdehyde and 4-hydroxyalkenals ( lipid peroxidation products ) . Secondary outcomes were changes in serum tumor necrosis factor-alpha ( TNF-alpha ) , interferon-gamma ( IFN-gamma ) and interleukin-10 ( IL-10 ) . RESULTS Statistically significant reductions in serum 4-hydroxyalkenals and malondialdehyde levels were observed in both groups in comparison with pretreatment values , but the patients who received Viusid showed a more marked reduction as compared with the control group ( P = 0.001 ) . TNF-alpha levels significantly increased from 6.9 to 16.2 pg/mL ( P < 0.01 ) in the patients who received placebo in comparison with almost unchanged levels , from 6.6 to 7.1 pg/mL ( P = 0.26 ) , in the patients treated with Viusid ( P = 0.001 ) . In addition , IL-10 levels were markedly increased in the patients treated with Viusid ( from 2.6 to 8.3 pg/mL , P = 0.04 ) in contrast to the patients assigned to placebo ( from 2.8 to 4.1 pg/mL , P = 0.09 ) ( P = 0.01 ) . Likewise , the administration of Viusid markedly increased mean IFN-gamma levels from 1.92 to 2.89 pg/mL ( P < 0.001 ) in comparison with a reduction in mean levels from 1.80 to 1.68 pg/mL ( P = 0.70 ) in the placebo group ( P < 0.0001 ) . Viusid administration was well tolerated . CONCLUSION Our results indicate that treatment with Viusid leads to a notable improvement of oxidative stress and immunological parameters in patients with chronic hepatitis OBJECTIVE We investigated the effects of vitamin E and C supplementation on the fatty acid composition of mononuclear cells and on the clinical observations in patients who had chronic hepatitis C and received interferon-alpha-2b ( IFN-alpha-2b ) and ribavirin combination therapy .  METHODS Patients were r and omly allocated to receive daily 500 mg of vitamin E and 750 mg of vitamin C ( vitamin group , n = 14 ) or no supplement ( non-vitamin group , n = 16 ) in addition to IFN-alpha-2b and ribavirin therapy . The fatty acid composition of mononuclear cell phospholipids was analyzed before and at 2 , 4 , and 8 wk after treatment . RESULTS After vitamin supplementation , plasma and red blood cell alpha-tocopherol and plasma ascorbic acid levels increased in the vitamin group . Serum levels of alanine aminotransferase decreased significantly after 2 wk of treatment in both groups . At the start of treatment , a lower level of eicosapentaenoic acid ( EPA ) and a higher level of the molar ratio of arachidonic acid to EPA in mononuclear cells were observed in the present patients compared with healthy volunteers , and a significant correlation between the molar ratio and serum alanine aminotransferase level was found . The EPA level of mononuclear cells was maintained in the vitamin group during treatment , whereas a significant decrease was observed in the non-vitamin group at 4 and 8 wk after treatment . CONCLUSIONS Antioxidant vitamin supplementation during IFN-alpha-2b and ribavirin therapy prevented a decrease in EPA of mononuclear cell phospholipids . If a further decrease in the ratio of arachidonic acid to EPA can be achieved by using oral EPA supplementation , the efficacy of IFN-alpha-2b and ribavirin therapy may be improved BACKGROUND / AIMS Severe alcoholic hepatitis is associated with high morbidity and short-term mortality .  Corticosteroids are the only widely used therapy but established contraindications to treatment or the risk of serious side-effects limit their use . The perceived need for alternative treatments together with the theoretical benefits of anti-oxidant therapy triggered the design of a r and omised clinical trial comparing these treatment modalities . METHODS One hundred and one patients were r and omized into a clinical trial of corticosteroids or a novel antioxidant cocktail with a primary endpoint of 30-day mortality . RESULTS At 30 days there were 16 deaths ( 30 % ) in the corticosteroid treated group compared with 22 deaths ( 46 % ) in the antioxidant treated group ( P=0.05 ) . The odds of dying by 30 days were 2.4 greater for patients on antioxidants ( 95 % confidence interval 1.0 - 5.6 ) . A diagnosis of sepsis was made more frequently in the AO group ( P=0.05 ) , although microbiologically proven episodes of infection occurred more often in the CS group ( P<0.01 ) . The survival advantage for corticosteroid treated patients was lost at 1 year of follow-up ( P=0.43 ) . CONCLUSIONS This study has shown that corticosteroids in the form of prednisolone 30 mg daily are superior to a broad antioxidant cocktail in the treatment of severe alcoholic hepatitis
BACKGROUND Several liver diseases have been associated with oxidative stress .
Accordingly , antioxidants have been suggested as potential therapeutics for various liver diseases .
The evidence supporting these suggestions is equivocal .
OBJECTIVES To assess the benefits and harms of antioxidant supplements for patients with liver diseases .