title: Management of hepatic encephalopathy with oral zinc supplementation: a long-term treatment. Zinc supplementation therapy improves the outcome of patients with chronic hepatitis C Effect of zinc on liver cirrhosis with hyperammonemia: a preliminary randomized, placebo-controlled double-blind trial. Effects of low dose zinc supplementation on biochemical markers in non-alcoholic cirrhosis: a randomized clinical trial. Preliminary study of combination therapy with interferon-α and zinc in chronic hepatitis C patients with genotype 1b Zinc supplementation enhances the response to interferon therapy in patients with chronic hepatitis C. The role of antioxidants and zinc in minimal hepatic encephalopathy: a randomized trial The effect of zinc supplementation on the treatment of chronic hepatitis C patients with interferon and ribavirin. ORAL ZINC SUPPLEMENTATION IMPROVES HEPATIC ENCEPHALOPATHY: Results of a Randomised Controlled Trial Triple therapy of interferon and ribavirin with zinc supplementation for patients with chronic hepatitis C: a randomized controlled clinical trial. Effect of zinc supplementation on viral response in patients with chronic hepatitis C and Beta thalassemia major, a pilot study. Zinc supplementation prevents the increase of transaminase in chronic hepatitis C patients during combination therapy with pegylated interferon alpha-2b and ribavirin. Zinc supplementation in alcoholic cirrhosis. A double-blind clinical trial.
abstract: OBJECTIVES The effect of long-term oral zinc supplementation , in addition to st and ard therapy ( protein-restricted diet and lactulose ) on recurrent hepatic encephalopathy , was assessed in a double-blind study . METHODS Ninety cirrhotic patients with stable recurrent hepatic encephalopathy , after following a one month period of st and ard therapy , were r and omized to receive oral zinc acetate supplementation ( 600 mg/day ) in addition to st and ard therapy or to continue only st and ard therapy ( a diet containing 0.8 g/kg/day of protein and 90 g/day of lactulose ) for six months . Psychometric tests , NCT ( number correction test ) and PSE ( portal-systemic encephalopathy ) Index , were used to evaluate the degree of hepatic encephalopathy , both at the beginning and the end of each treatment period . RESULTS Oral zinc supplementation in addition to st and ard therapy was able to normalize serum zinc levels .  The patients who never showed clinical signs of hepatic encephalopathy during the trial were 88.6 % in zinc-group and 86 % in only st and ard therapy group . Psychometric tests , NCT and PSE Index , were statistically better than basal values either in zinc-group or in only st and ard therapy group . CONCLUSIONS Final values of psychometric tests were better in zinc-group than only st and ard therapy group but the differences were not statistically significant We administered zinc supplementation therapy over three years to patients with chronic hepatitis C and reported and that the aspartate aminotransferase ( AST ) and alanine aminotaransferase ( ALT ) levels decreased , and platelet counts increased , significantly in the group with increased serum zinc concentrations . We are continuing this treatment to clarify the long-term consequences and report here the changes in serum zinc concentrations over seven years and compare the cumulative incidence of hepatocellular carcinoma ( HCC ) . We administered polaprezinc to 32 patients , r and omly selected for zinc therapy ( treatment group ) , while another 30 formed the control group . We measured the serum zinc and albumin concentrations and conducted a prospect i ve study to determine long-term outcomes . The changes and rates of change of serum zinc concentrations after seven years were 76.7 ± 18.2 µg/dl and + 0.302 ± 0.30 % in the treatment group and 56.7 ± 12.4 µg/dl and + 0.033 ± 0.21 % in the control group and had increased significantly ( p = 0.0002 , p = 0.0036 ) . Progression of liver disease seemed to vary , depending on serum albumin concentrations . In the group with baseline serum albumin concentrations of 4.0 g/dl or more , the change and rate of change of serum zinc concentrations increased significantly , and the cumulative incidence of HCC tended to decrease , in the treated group . According to multivariate analysis , the factors that contribute to a reduction in the incidence of HCC are  zinc therapy ( risk ratio : 0.113 , 95 % CI : 0.015–0.870 , p = 0.0362 ) , and platelet counts ( 0.766 , 0.594–0.989 , 0.0409 ) . Zinc supplementation therapy seems to improve liver pathology and reduce the incidence of HCC OBJECTIVE To our knowledge , no r and omized study has shown whether zinc replacement therapy is effective for hyperammonemia in liver cirrhosis ; therefore , we performed a double-blind , placebo-controlled trial to examine efficacy and safety of the zinc replacement therapy . METHODS Patients with liver cirrhosis and hyperammonemia ( at or above the institutional reference value ) and hypozincemia ( ≤65 μg/dL ) were enrolled in the outpatient units of the participating institutions and were r and omly divided to receive placebo ( P group ) or zinc acetate preparation at a dose of 3 capsules/d for a total zinc content of 150 mg/d ( Z group ) by the envelope method . Of the 18 enrolled patients , 6 dropped out ; thus , the analyses included 12 patients ( 5 in the P group and 7 in the Z group ) . Variations in blood concentrations of zinc and ammonia as well as liver function test results were compared . RESULTS Blood zinc levels significantly increased in the Z group ( P = 0.0037 ; Friedman test ) but not the P group . Blood ammonia levels significantly decreased in the Z group ( P = 0.0114 ; Friedman test ) but not the P group . The percent change in blood ammonia level also revealed significant reduction at the eighth week in the Z group ( P = 0.0188 : Mann-Whitney test ) . No serious adverse events attributable to the zinc preparation were noted . CONCLUSION Although this study is preliminary and includes a small sample , it is , to our knowledge , the first r and omized controlled trial to show that zinc supplementation for 3 mo seems effective and safe for treating hyperammonemia in liver cirrhosis . Studies with a larger sample size are needed to confirm our findings BACKGROUND The present study aim ed to evaluate the effects of low dose zinc ( Zn ) supplementation on biochemical markers and underlying disease status in non-alcoholic cirrhotic patients . METHODS We enrolled 60 cirrhotic patients in a double-blind ,  placebo-controlled  , r and omized clinical trial . All patients in the interventional group ( n = 30 ) received long-term , low dose Zn supplementation ( 50 mg elemental Zn sulfate daily ) . The control group ( n = 30 ) received placebo ( starch ) .  Child-Pugh scores and biochemical markers were assessed for both interventional and control groups at the first day and the end of the 90th day of the interventional period . A per- protocol analysis was performed after excluding all participants who did not receive or complete the r and omized intervention . The mean differences of quantitative variables between and within groups were evaluated by independent sample s t-test and paired- sample s t-test , respectively . SPSS version 13.00 was used for statistical analysis . RESULTS In the initial evaluation , 16 ( 53.30 % ) patients from the interventional group had a Child-Pugh score of 5 - 8 and 14 ( 46 . 70 % ) had a score of 9 - 12 . In the control group 18 ( 60.00 % ) had a Child-Pugh score of 5 - 8 and 12 ( 40.00 % ) scored 9 - 12 . After three months the mean Child-Pugh score in the interventional group showed a significant improvement ( from 6.56 ± 0.21 to 5.72 ± 0.22 , P = 0.001 ) whereas in the control group despite no significant decline , the mean Child-Pugh score increased slightly ( from 6.25 ± 0.27 to 6.67 ± 0.31 , P = 0.14 ) . Zn supplementation significantly decreased copper ( Cu ; P = 0.01 ) and creatinine ( Cr ; P < 0.0001 ) levels . CONCLUSION In this study , we determined that low dose Zn supplementation could prevent deterioration of clinical status of cirrhosis and prevent excess Cu accumulation in non-alcoholic cirrhotic patients . Zn supplementation produces metabolic effects and trends towards improvements in liver function , hepatic encephalopathy , and nutritional status . Registration ID in I RCT : I RCT 201106122017N4 We have evaluated the efficacy of  interferon-α ( IFN-α ) plus zinc therapy  in hepatitis C patients with genotype 1b , poor responders for IFN alone . Ten patients were injected with 10 MU of IFN-α every day for 4 wk , followed by three times a week for 20 wk ( control group ) . Nine patients took 300 mg of zinc sulfate a day orally during IFN-α therapy ( zinc sulfate group ) , and 15 patients took IFN-α and 150 mg of polaprezinc ( polaprezinc group).On the d 8 of IFN therapy , circadian zinc levels in serum elevated significantly in the polaprezinc group compared to the zinc sulfate group or control group . Serum ALT levels normalized in 73.3 % of the polaprezinc group , 55.6 % of the zinc sulfate group , and 40.0 % of the control group at 6 mo after the end of IFN therapy . Sustained eradication for the hepatitis C virus RNA judged at the end of the 6-mo follow-up period was higher in the polaprezinc group than in the zinc sulfate group ( 53.3 % vs 11.1 % , p<0.05 ) or the control group ( 20.0 % ) . No clinical side effects of zinc were observed at the dose used . The data suggest that polaprezinc is expected to increase the therapeutic response of IFN-α for chronic hepatitis C with genotype 1b We evaluated the synergistic effect of zinc supplementation on the response to interferon ( IFN ) therapy  in patients with intractable chronic hepatitis C in a pilot study using natural IFN-alpha with or without zinc . No clinical differences were observed between patients treated with IFN alone ( n=40 ) and IFN with polaprezinc ( IFN + Zn , n=35 ) . All patients were positive for HCV genotype Ib and had more than 105 copies of the virus/mL serum .  Ten million units of natural IFN-alpha was administered daily for 4 weeks followed by the same dose every other day for 20 weeks . In the IFN + Zn group , patients received an additional dose of 150 mg/day polaprezinc orally throughout the 24-week IFN course . No additional side-effects of polaprezinc  were noted but four out of 40 IFN alone treatment and three out of 35 IFN + Zn group withdrew because of side-effects . Complete response ( CR ) was defined as negative HCV RNA in the serum on PCR and normal aminotransferase level 6 months after therapy . Incomplete response ( IR ) was normal liver enzyme and positive serum HCV RNA . Both of them were evaluated at the 6 months after the completion of the treatment . Patients with higher levels of serum HCV ( more than 5 x 105 copies/mL ) had little response in both treatment groups . Patients with moderate amount of HCV ( 105 to 4.99 x 105/mL ) showed high response rates in combination group ( CR : 11/27 , 40.7 % ; CR + IR 15/27 , 64.3 % ) , better than IFN alone ( CR : 2/15 , 18.2 % ; CR + IR : 2/15 , 18.2 % ) . Serum zinc levels were higher in patients with IFN + Zn group than in the IFN group . Our results indicate that zinc supplementation enhances the response to interferon therapy  in patients with intractable chronic hepatitis Background : Minimal hepatic encephalopathy ( MHE ) has a far-reaching impact on quality and function ability in daily life and may progress to overt hepatic encephalopathy . There is a synergistic effect between systemic oxidative stress and ammonia that is implicated in the pathogenesis of hepatic encephalopathy . The aim of this study is to investigate the effectiveness of oral supplementation of antioxidants and zinc gluconate on MHE versus lactulose . Methods : Our study included 58 patients with cirrhosis diagnosed as having MHE by neuropsychometric tests , including  number connection test part A ( NCT-A ) , digit symbol test ( DST ) and block design tests ( BDTs ) . Patients were r and omized to receive 175 mg zinc gluconate , 50,000 IU vitamin A , 500 mg vitamin C and 100 mg vitamin E once daily plus lactulose , dose 30–60 ml/day for 3 months [ group A ( n = 31 ) ] or initiated and maintained on lactulose dose 30–60 ml/day for 3 months [ group B ( n = 27 ) ] . Neuropsychometric tests and laboratory investigations were repeated after 3 months of therapy . Results : Compared with the baseline neuropsychometric tests , a significant improvement was reported in patients with MHE after 3 months of antioxidant and zinc therapy ( group A ) versus patients with lactulose therapy ( group B ) ( NCT-A , p < 0.001 ; DST , p = 0.006 ; BDT , p < 0.001 ) . Antioxidant and zinc supplementation significantly decreased arterial ammonia level , alanine aminotransferase ( ALT ) , aspartate aminotransferase ( AST ) ( p < 0.001 ) and improved Child – Pugh score in MHE after 3 months of therapy ( p= 0.024 ) . Conclusion : Antioxidant and zinc supplementation can improve MHE in patients with liver cirrhosis OBJECTIVES To evaluate the effects of zinc supplementation on serum zinc and copper levels , and the severity of adverse reactions and virologic responses in chronic hepatitis C patients undergoing interferon (IFN)/ribavirin therapy . DESIGN AND METHODS Forty subjects were r and omly assigned to receive IFN-alpha-2a/ribavirin with or without zinc gluconate for 24 weeks , then a period of 6 months for follow-up . Twenty healthy controls were also enrolled in the study . Blood sample s were collected at different time points during therapy and at 6 months after the completion of therapy and were analyzed for zinc and copper levels . The adverse reactions and the virologic responses were also examined accordingly . RESULTS Serum zinc levels were significantly lower in chronic hepatitis C patients than in healthy controls and further depressed by IFN/ribavirin treatment . However , serum zinc levels in patients were remediable by zinc supplements . No apparent difference was seen in virologic responses between subjects with or without zinc supplements , but certain adverse side effects associated with the zinc therapy were significantly decreased . CONCLUSIONS Zinc supplementation may be a complementary therapy in chronic hepatitis C patients to increase the tolerance to IFN-alpha-2a and ribavirin 22 cirrhotic patients with chronic encephalopathy were given oral zinc supplementation or placebo in a double-blind r and omised trial . In the group which received zinc acetate 600 mg a day for 7 days , serum zinc had been restored to normal by day 8 . On day 8 hepatic encephalopathy , as assessed by a trailmaking test , was improved in the supplemented group but not in the placebo group . There was also a significant increase in blood urea nitrogen in the supplemented group . Short-term oral zinc supplementation probably improved hepatic encephalopathy by correcting the zinc deficiency that compromises conversion of ammonia to urea . The duration of this improvement requires further investigation AIM To study the therapeutic effect of interferon ( IFN ) and ribavirin with zinc supplement on patients with chronic hepatitis C viral ( HCV ) infection . METHODS A total of 102 patients confirmed histologically to have chronic HCV infection with genotype 1b and more than 100 KIU/mL of HCV were r and omly assigned to each arm of the study and each received 10 million units of pegylated interferon ( IFN-alpha-2b ) daily for 4 wk followed by the same dose every other day for 20 wk plus ribavirin ( 600 or 800 mg/d depending on body weight ) , with or without polaprezinc ( 150 mg/d ) orally for 24 wk . The primary endpoint was sustained virological response ( SVR ) defined as negative HCV-RNA in the serum 6 mo after treatment . RESULTS There were no differences in the clinical background between the two groups except for more females in the dual therapy group than in the other group ( P<0.05 ) . SVR was observed in 33.3 % of the triple therapy group and 33.3 % of the dual therapy group . The side effects were almost the same in both groups except for gastrointestinal symptoms , which were less in the triple therapy group ( P=0.019 ) . CONCLUSION Considered together , triple therapy of zinc plus IFN and ribavirin for HCV infection patients with genotype 1b and high viral load is not better than dual therapy except for lower incidence of gastrointestinal side effects INTRODUCTION Zinc deficiency has been reported in patients with both hepatitis C and beta thalassemia major .  Zinc supplementation in addition to antiviral therapy of chronic hepatitis C has been accompanied by some success in patients with chronic hepatitis C. OBJECTIVE The aim of the present pilot study is to determine the effect of 30 mg elemental zinc on biochemical and virological response in a population of patients with chronic hepatitis C with beta thalassemia major . MATERIAL S AND METHODS A prospect i ve , double blind , placebo controlled trial included 40 patients being treated with Pegylated interferon Alfa ( Peg IFN-α ) and ribavirin .  Biochemical and virological parameters and plasma zinc levels were determined before starting treatment . Patients were r and omly selected to receive either zinc or a placebo in addition to Peg IFN-α and ribavirin for a period of one year . AST , ALT , sustained viral response ( SVR ) , and zinc levels were measured after treatment . Of the original 40 eligible patients , eight withdrawn from the study and 32 patients completed the study ; 16 in the zinc group and 16 in the placebo group . Analysis of the data shows that there is no difference between the two groups in AST , ALT , SVR or zinc level following one year of treatment ( p=0.224 , p=0.616 , p=0.670 , p=0.999 , respectively ) . CONCLUSION The results of this study indicate that using 30 mg/day elemental zinc did not significantly improve the outcome of treatment in thalassemia patients with chronic hepatitis C. In future studies , we recommend trying higher doses zinc in patients with hepatitis C who had beta thalassemia major We investigated the effects of zinc supplementation on clinical observations in chronic hepatitis C patients receiving pegylated interferon ( PEG-IFN ) alpha-2b plus ribavirin combination therapy . Patients were r and omly allocated to receive 150 mg polaprezinc ( zinc group , n=11 ) or no supplement ( control group , n=12 ) daily in addition to PEG-IFN alpha-2b plus ribavirin therapy and 300 mg vitamin E and 600 mg vitamin C supplementation daily for 48 wk . Among the patients who continued treatment , the serum alanine aminotransferase ( ALT ) level at 12 wk in the zinc group was significantly lower than that in the control group . All patients in the zinc group ( 9/9 ) and 67 % ( 8/12 ) of the control patients at 24 wk , and all patients in the zinc group ( 7/7 ) and 60 % ( 6/10 ) of the control patients at 48 wk showed a decrease in serum ALT levels to within the normal range ( 7 - 44 U/L ) . HCV RNA disappeared in all patients ( 7/7 ) in the zinc group and in 8 of 10 control patients at 48 wk . Polaprezinc supplementation decreased plasma thiobarbituric acid reactive substances and prevented the decrease of polyunsaturated fatty acids of erythrocyte membrane phospholipids . No significant differences were observed in the dosage of medicines or other clinical data during the treatment . These observations indicate that polaprezinc supplementation may have induced some antioxidative functions in the liver which result ed in reduced hepatocyte injury during PEG-IFN alpha-2b plus ribavirin therapy A double-blind clinical trial with zinc sulfate , 0.2 g three times daily , and a placebo was performed in 30 patients with biopsy-proven alcoholic liver cirrhosis . The disease was in a stable phase , and none of the patients showed evidence of a decompensated liver function . Parameters of liver function , taste acuity , dark adaptation and of zinc and vitamin A metabolism were followed for six weeks . In the zinc-treated group of 16 patients , serum zinc rose from a normal mean value of 13.3 to 17.4 mumol/l , whereas the mean serum vitamin A level remained practically unaltered within the normal range , 1.89 at the entry and 1.83 mumol/l at the end of the study . Plasma prothrombin and serum alkaline phosphatase levels of the zinc group increased and serum bilirubin and serum carotene decreased significantly . The dark adaptation did not change , but the taste function was significantly improved during zinc treatment . The results indicate that zinc supplementation causes alleviation of certain abnormalities of cirrhotics , which deserves further attention
target: Clinical trials assessing zinc supplementation in liver diseases do not show benefits in terms of clinical improvement or disease halting .
  There are possible benefits of zinc supplementation on hepatic encephalopathy , however , this is based on limited evidence .
background: INTRODUCTION AND OBJECTIVES Zinc deficiency has been associated with poor prognosis in chronic liver disease .
  This systematic review and meta- analysis aim ed to evaluate the role of zinc supplementation in the management of chronic liver diseases .