Clinical trial: oral zinc in hepatic encephalopathy
|
|
- Vanessa Ryan
- 8 years ago
- Views:
Transcription
1 Alimentary Pharmacology and Therapeutics Clinical trial: oral zinc in hepatic encephalopathy Y. Takuma*,, K. Nouso à, Y. Makino, M. Hayashi & H. Takahashi *Department of Gastroenterology, Kurashiki Central Hospital, Okayama, Japan. Department of Internal Medicine, National Hospital Organization Iwakuni Center, Yamaguchi, Japan. à Department of Molecular Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. Department of Clinical Research, National Hospital Organization Iwakuni Clinical Center, Yamaguchi, Japan. Correspondence to: Dr Y. Takuma, Department of Gastroenterology, Kurashiki Central Hospital, Miwa, Kurashiki, Okayama , Japan. Publication data Submitted 5 June 2010 First decision 23 June 2010 Resubmitted 11 August 2010 Accepted 13 August 2010 EV Pub Online 3 September 2010 SUMMARY Background Hepatic encephalopathy has a negative effect on patient health-related quality of life (HRQOL). Zinc supplementation has been effective with regard to altered nitrogen metabolism. Aim To investigate the effectiveness of oral zinc supplementation on hepatic encephalopathy and HRQOL. Methods Seventy-nine cirrhotic patients with hepatic encephalopathy were randomized to receive 225 mg of polaprezinc in addition to standard therapies of a protein-restricted diet including branched-chain amino acid and lactulose, or to continue only standard therapies for 6 months. The change of HRQOL by Short Form-36, hepatic encephalopathy grade, laboratory parameters, and neuropsychological (NP) tests were compared at baseline and at 6 months. We also evaluated via multivariate analysis whether zinc supplementation and clinical variables correlated with the changes in physical component scale (PCS) and mental component scale (MCS) between the two visits. Results Zinc supplementation significantly improved the PCS (P = 0.04), but not the MCS (P = 0.95). Zinc supplementation significantly decreased hepatic encephalopathy grade and blood ammonia levels (P = 0.03 and P = 0.01), and improved Child-Pugh score and NP tests compared with standard therapy (P = 0.04 and P = 0.02). In multivariate analysis, zinc supplementation was significantly associated with improvement in PCS (P = 0.03), whereas it was not significantly associated with change in MCS (P = 0.98). Conclusion Zinc supplementation is effective in hepatic encephalopathy and consequently improves patients HRQOL. Aliment Pharmacol Ther 2010; 32: doi: /j x
2 Clinical trial: oral zinc in hepatic encephalopathy INTRODUCTION Hepatic encephalopathy (HE) is a common neuropsychiatric complication of liver disease affecting about 20 30% patients with cirrhosis. 1 HE in patients with liver cirrhosis represents a significant reduction in health-related quality of life (HRQOL) and a reversible decline in cognitive function. 2 The pathogenesis of HE is not completely understood, but ammonia is considered to play a key role. 3 Most studies have demonstrated that reduction in blood ammonia level affected improvements in HE grade and neuropsychological tests. Improvement in cognitive functions may lead to improvement in HRQOL. HRQOL is a major outcome in the evaluation of treatments for HE because HE itself is a poor prognostic factor in cirrhotic patients. Whether treatment of HE by a reduction in ammonia level is associated with health benefits has not been well established. Synthetic disaccharides such as lactulose and lactitol have been used as the main agents to treat HE in advanced cirrhosis. A recent randomized control trial suggested that lactulose improved HRQOL in minimal HE patients; 4 however, some patients were known to be unresponsive to these agents, because it minimized ammonia absorption, but did not affect ammonia detoxification. Branched-chain amino acid (BCAA) may be another therapy for HE. Some studies 5, 6 have shown that oral BCAA supplements reduced significantly the incidence of complications including HE and improved HRQOL in advanced cirrhotic patients. In advanced cirrhosis, amino acid imbalance due to functional disorder of ammonia disposal via urea synthesis in the liver, and consumption of BCAA caused by ammonia disposal via glutamine synthesis in the skeletal muscle was observed. 7 However, BCAA alone sometimes increased the blood ammonia levels in protein-intolerant patients. 8 Zinc supplementation was considered to be another important therapeutic option of HE, because its supplementation significantly improved HE, which had been refractory to protein restriction, and lactulose Liver cirrhotic patients with HE are associated with a high incidence of zinc deficiency, which contributes to nitrogen metabolism disorder. 12 The causes of low serum zinc levels in advanced cirrhotic patients are thought to be poor dietary intake via protein-restricted diet, impaired intestinal absorption, and excessive urinary losses. Two major organs are involved in ammonia metabolism: the liver, in which ammonia is converted to urea via ornithine transcarbamylase (OTC), and the skeletal muscle, where ammonia is disposed with glutamic acid via glutamine synthetase. 13 In animal models, zinc deficiency decreases the activity of OTC, and zinc supplementation produces a remarkable increase in hepatic OTC. 14 Zinc deficiency was also reported to impair the activity of muscle glutamine synthetase, 15 which leads to hyperammonaemia. Therefore, zinc supplementation in addition to standard therapies with lactulose and a protein-restricted diet including BCAA may enhance the hepatic conversion of amino acids into urea, 10 decrease serum ammonia, and consequently improve HRQOL. A randomized control study was carried out to determine the influence of zinc supplementation on HRQOL and psychomotor performance of HE patients unresponsive to standard therapies. MATERIALS AND METHODS Design of the study Ours is a prospective randomized study comparing the effect of zinc supplementation on HE and HRQOL in patients with decompensated liver cirrhosis treated with BCAA and synthetic disaccharides. The length of the study is 6 months. Enrolment was from December 2005 to September 2007, and conducted at the National Hospital Organization Iwakuni Clinical Center. Written informed consent was obtained from all patients. This study was conducted according to the Declaration of Helsinki and approved by the investigation and ethics committee of the hospital. Setting and participants Inclusion criteria of this study were as follows: (i) patients with liver cirrhosis diagnosed histologically or clinically at least 3 months before enrolment, and under treatment with oral BCAA granules (Livact Granules; Ajinomoto Co., Inc., Tokyo, Japan; 12 g per day of BCAA; L-isoleucine 2856 mg, L-leucine 5712 mg, and L-valine 3432 mg); (ii) hyperammonaemia (fasting venous ammonia concentration at fasting 370 lg dl); and (iii) patients with grade 1 or 2 recurrent episodic HE unresponsive to standard therapies with ml per day of lactulose and a protein-restricted diet (1.0 g kg day of protein including BCAA preparation) for at least 4 weeks. Exclusion criteria were as follows: (i) incurable hepatocellular carcinoma (HCC) (curable HCC conforming to the Milan criteria, 16 and receiving treatments with radiofrequency ablation therapy, or surgical resection); (ii) alcoholic cirrhosis with inability to abstain from alcohol for at least 1 year before enrolment; (iii) severe Aliment Pharmacol Ther 2010; 32:
3 Y. Takuma et al. complications of cirrhosis including serum albumin concentration <2.5 g dl, serum total bilirubin concentration 33.0 mg dl, or recurrent HE graded 3 or higher; (iv) use of antibiotics, drugs affecting psychometric performances (benzodiazepines, antiepileptics, psychotropic drugs, or narcotics); (v) history of gastrointestinal bleeding; (vi) history of shunt surgery, transjugular intrahepatic portosystemic shunt, or balloon-occluded retrograde transvenous obliteration; (vii) age >80 years; and (viii) organic neurological diseases such as subdural haematoma, Wernicke s disease, encephalitis, other metabolic abnormalities, and drug intoxications. 17 Male patients were considered to have alcohol-related cirrhosis if daily alcohol intake was more than 80 g; female patients, over 30 g for more than 5 years, if testing showed no viral, metabolic, or immunological cause. Viral hepatitis was diagnosed when HCV antibody or hepatitis B surface antigen was positive. Randomization and interventions Patients enrolled in this study were randomly assigned in a 1:1 ratio either to receive 225 mg (containing 51 mg of zinc and 174 mg of L-carnosine) per day of polaprezinc (Zeria Pharmaceutical Co., Ltd., Tokyo, Japan) in addition to ongoing standard therapies of a protein-restricted diet including BCAA and lactulose (zinc group), or to continue only standard therapies (control group) for 6 months. All other medications (diuretics, lactulose, and BCAA) and a protein-restricted diet were continued unchanged throughout. The polaprezinc is a drug provided as granules, and it was really difficult to make the placebo with similar taste and dosage of the form. For these reasons, the study was not blinded, and randomization was performed using computer-generated tables to assign patients to receive either polaprezinc or standard treatment. Minimization method to adjust the baseline imbalance between 2 groups in the composition of the HE grade (1 vs. 2) and that between inpatients and outpatients was used. Treatment allocation was concealed from the scorer (M.H.), but not from the principal investigator (Y.T.). Evaluations of HE grade and HRQOL During the selection period, the patients with an overt episode of HE were treated as in-patients or out-patients depending on the severity of HE episodes. In particular, out-patients were evaluated at every weekly interval. Recurrent episodic HE was defined as at least three episodes of overt HE in a 1-month period despite continuous treatment with lactulose and a protein-restricted diet. Diagnosis and grading of the overt HE were based on the clinical and neuropsychological abnormalities using the West Haven Criteria 18 including state of consciousness, intellectual function, personality behaviour and neuromuscular abnormalities. Finally, diagnosis and grading of HE were decided by two senior hepatologists after consultation with an expert neurologist. Number connection test (NCT) 19 and digit symbol test (DST) 20 were applied as neuropsychological (NP) tests for HE. For NCT-A, patients were asked to connect figures from 1 to 20 serially that were scattered on a page as quickly as possible (time limit: 120 s). For NCT- B, patients were asked to connect figures from 1 to 10 with ten Japanese characters scattered on a page as quickly as possible (time limit: 180 s). A low score indicated good performance. DST was included in the Wechsler adult intelligence scale-revised. The individuals were given a list of digits from 1 to 9 associated with symbols and asked to fill in the blanks with symbols that corresponded to each number. The test scores were the total correctly sequential matched symbols with those within a 60-s interval (maximum no. questions: 40). A high score indicated good performance. Abnormal values of NCT-A, NCT-B, and DST were determined based on upper and lower 10th percentiles, which are regarded as outliers in healthy Japanese subjects obtained at 5-year intervals. 21 NCT-A, NCT-B, and DST results were affected by age, but not by gender, facility, or education (most of the Japanese population receives compulsory education for at least 9 years). The primary endpoints are 6-month changes of the physical component scale (PCS) in the SF-36 version 2 22, 23 questionnaires; these outcomes were chosen as a previous study 24 indicated that PCS is more likely affected by HE than mental health domains. SF-36 was used to gather information on general quality of life on eight domains of health: 25 (i) Physical functioning (PF), (ii) Role-physical (RP), (iii) Bodily pain (BP), (iv) General health (GH), (v) Vitality (VT), (vi) Social functioning (SF), (vii) Role-emotional (RE) and (viii) Mental health (MH). The score on each scale ranges from 0 to 100, with lower scores indicating poor health or greater disability. Two standardized summary scores, the PCS and the mental component scale (MCS), were calculated from SF-36 raw data. 26 It has also proven useful for QOL evaluation in patients with advanced liver disease. 24 The secondary endpoints are 6-month changes in HE grade, other clinical parameters, NP tests and any symptoms included in adverse events Aliment Pharmacol Ther 2010; 32:
4 Clinical trial: oral zinc in hepatic encephalopathy Follow-up Clinical evaluation and laboratory values, adverse events and adherence to trial medication were assessed in both groups at 1-month intervals during the study period. Both the patients and their relatives were instructed on the importance of contacting medical staff immediately in the event of any alteration in the patient s mental state between the scheduled visits. An independent scorer, unaware of assignment, assessed participants via a battery of NP tests, and the SF-36 questionnaire at baseline and at 6 months. All patients received dietary assessment and advice from a study dietician at baseline and 3 months. Patients were regarded as responders if they had at least 1 degree of improvement in HE grade at the end of study period. In addition, patients were regarded as nonresponders if they had aggravation or no change in HE grade at the end of study period. Statistical analysis For the randomized cohort, we determined that a sample size of 39 patients in each arm was needed to detect a 20% of PCS score increased in zinc treatment compared with standard treatment with a 5% (2-tailed) for a error and 80% for b error. 27 Standard deviation (s.d. = 13.0) and 20% (5.9 of changes in PCS score) of expected effect size were derived from our preliminary study (unpublished data). The Mann Whitney U-test, chi-square test, and Fisher s exact test were used to analyse the differences in baseline data between the two groups. Spearman s rank correlation was used to evaluate association among the two summary scores of the SF-36 and continuous clinical parameters. ANOVA was performed to detect association between the two summary scores of the SF-36 and clinical binary data. In an attempt to explore independent predictors of the 6-month changes in two summary scores of the SF- 36, all univariate variables were entered into stepwise backward multiple linear regression analyses, and variables with P values less than 0.1 were retained in the multivariate model. A comparison of serum laboratory values before and after treatment was studied using Student s paired t-test, and on the rate of abnormal NP tests before and after treatment using McNemar s test. Change in each clinical parameter between two groups was analysed using ANOVA. Study outcomes were analysed using an intention-to-treat (ITT) population. A P value of less than 0.05 was considered statistically significant. Statistical analyses were performed using SPSS 16.0J for Windows (SPSS Inc. and Microsoft Corp., Chicago, IL, USA). RESULTS Trial enrolment During the study period, 156 cirrhosis patients with overt HE were screened; 79 (51%) meeting eligibility criteria were enrolled (Figure 1). Thirty-nine patients with HE were assigned to zinc supplementation in addition to standard therapy, and 40 patients continued only standard therapy for 6 months. Reasons for exclusion (77 patients: 49%) included refusal to participate (6 patients), Enrolment Allocation Follow-up 156 cirrhosis patients with overt HE screened Zinc supplementation for 6 months (zinc group, n = 39) None lost at follow-up 79 enroled Randomization No zinc supplementation (control group, n = 40) 1 lost at follow-up 1 death 77 excluded 71 not meeting inclusion criteria 6 refused to participate Analysis 39 analyzed 38 analyzed Figure 1 Flowchart demonstrating participants throughout the study procedures. Aliment Pharmacol Ther 2010; 32:
5 Y. Takuma et al. advanced HCC (21 patients), complicated chronic recurrent HE grade 3 or higher (10 patients), recent gastrointestinal bleeding (10 patients), serum albumin concentration <2.5 g dl (8 patients), serum total bilirubin concentration 33.0 mg dl (6 patients), history of recent alcohol intake (5 patients), recent antibiotic use (5 patients), recent use of drugs affecting psychomotor performance (3 patients), unfit to perform NP tests due to severe involuntary movements such as tremor (2 patients) and history of balloon-occluded retrograde transvenous obliteration (1 patient). Baseline characteristics Clinical and demographic characteristics are shown in Table 1. Causes of cirrhosis were chronic viral hepatitis (58 patients), alcoholic liver injury (13 patients), primary biliary cirrhosis (3 patients), autoimmune hepatitis (2 patients) and cryptogenic cirrhosis (3 patients). There were no statistically significant differences between the zinc and control groups with respect to baseline characteristics. Zinc deficiency (plasma zinc concentration <70 lg dl) was observed in 38 patients (97%) in the zinc group, and 38 patients (95%) in the control group. Baseline values of individual domains and summary scores of SF-36 did not differ significantly between groups (Table 2). Clinical course Thirty-nine zinc-assigned patients (zinc group) completed the study; one patient discontinued due to an adverse event (nausea and vomiting), and the rest received the full amount of supplement prescribed during the study Table 1 Characteristics of the zinc group and control group at baseline Characteristic Total (n = 79) Control group (n = 40) Zinc group (n = 39) P value Gender (male female) Age (years) Hospital admission (in-patients out-patients) Cause of cirrhosis (viral alcoholic others) Child-Pugh score Child-Pugh classification (A B C) Modified Child-Pugh score MELD score Ascites (present absent) HE Grade (1 2) No. of HE episodes per patient Oesophageal varices (present absent) History of HCC (present absent) Total bilirubin (mg dl) Albumin (g dl) Prothrombin time (%) Ammonia (lg dl) Platelets ( 10 4 ll) Zinc (lg dl) Fischer ratio Use of diuretics (yes no) Use of beta-blockers (yes no) MELD, model for end-stage liver disease; HE, hepatic encephalopathy; HCC, hepatocellular carcinoma. Values expressed as mean s.d. The Mann Whitney U-test, Chi-square test and Fisher s exact test were used to analyse the differences in background and biochemical data between the two groups. Modified Child-Pugh score: qualitative HE assessment was excluded from the Child-Pugh score (a range of 4 12) Aliment Pharmacol Ther 2010; 32:
6 Clinical trial: oral zinc in hepatic encephalopathy Table 2 SF-36 and NP tests of the zinc group and control group at baseline SF-36 Total (n = 79) Control group (n = 40) Zinc group (n = 39) P value PF RP BP GH VT SF RE MH PCS MCS NCT-A (s) NCT-A (abnormal normal) NCT-B (s) NCT-B (abnormal normal) DST (points) DST (abnormal normal) Mean numbers of abnormal NP tests PF, physical functioning; RP, role-physical; BP, bodily pain; GH, general health; VT, vitality; SF, social functioning; RE, role-emotional; MH, mental health; PCS, physical component scale; MCS, mental component scale; NCT, number connection test; DST, digit symbol test; NP test,neuropsychological test. Values expressed as mean s.d. The Mann Whitney U-test was used to analyse the differences between the two groups. period. Forty non-zinc treatment patients (control group) were also enrolled. One developed liver failure caused by bleeding oesophageal varices, and died at 3 months, and one dropped out at 4 months (Figure 1). Ultimately, 38 control group patients received the full amount of supplement prescribed during the study period. Noncompliance with assignment was not observed in either group, and none was excluded from statistical analysis. During the study period, all other medications (diuretics, lactulose, and BCAA) were continued unchanged, but two patients in the zinc and five in the control group developed severe HE (grade 3 or 4), and these patients were treated with kanamycin in addition to these medications until remission state. Impact of zinc supplementation on HRQOL Figure 2 shows the impact of treatment with zinc supplementation on SF-36. RP and PCS in the zinc group significantly improved after 6 months (P = 0.04 and P = 0.02 respectively); however, there was no significant change in the control group. Significant improvements in PF, RP and PCS in the zinc group were found compared to the control group (P = 0.04, P < 0.01, and P = 0.04 respectively, ANOVA); however, there was no significant improvement in other variables compared with the control group (P = 0.95, ANOVA) (Figure 2). Impact of zinc supplementation on clinical and laboratory parameters In the zinc group, the Child-Pugh and modified Child- Pugh score, mean HE grade and mean HE episodes improved (P < 0.001, P = 0.02, P < 0.01, and P < respectively), serum albumin level and serum zinc level increased (P = 0.02, and P < respectively), and blood ammonia level decreased (P < ) (Table 3). Moreover, the rate of presence of ascites showed a tendency to decrease in the zinc group (P = 0.08, McNemar s test). No significant changes in the serum laboratory values were observed in the control group. Significant difference in the Child-Pugh score, mean HE grade, mean HE episodes, blood ammonia level and serum zinc level was observed between the two groups at 6 months after Aliment Pharmacol Ther 2010; 32:
7 Y. Takuma et al. The 6-month changes from baseline in SF-36 scores 20 Control group Zinc group * 10 * 0 10 PF RP BP GH VT SF RE MH PCS MCS Figure 2 The 6-month changes from baseline (mean S.E.M.) in individual domains and summary scores of healthrelated quality of life (SF-36) in patients with cirrhosis randomized to control (open bars) and zinc (solid bars) groups. *Statistically significant (P < 0.05) compared with each value prior to treatment, as determined via Student s paired t-test. Statistically significant (P < 0.05), compared between zinc and control groups via ANOVA. Abbreviations: PF, physical functioning; RP, role-physical; BP, bodily pain; GH, general health; VT, vitality; SF, social functioning; RE, role-emotional; MH, mental health; PCS, physical component scale; MCS, mental component scale. therapy (P = 0.04, P = 0.03, P = 0.02, P = 0.01, and P < respectively, ANOVA). The rate of zinc deficiency decreased significantly after 6 months of zinc administration (P < 0.001, McNemar s test). However, no significant change was observed in the control group (P = 0.10, McNemar s test). HE improved in 21 patients (responders) in the zinc group, and 10 patients in the control group at the end of study period (54% vs. 26%, P = 0.03, Chi-square test). Furthermore, 16 patients in the zinc group improved to grade 0 HE, and six patients in the control group improved to grade 0 HE at the end of study period (41% vs. 16%, P = 0.02, Chi-square test). The mean value of each NP test was improved by zinc administration (NCT-A, P < ; NCT-B, P < 0.001; DST, P < 0.01, ANOVA) and differences between the two groups at 6 months after treatment were also statistically significant (NCT-A, P < 0.01; NCT-B, P < 0.01; DST, P = 0.02, ANOVA) (Table 3). Moreover, the frequency of an abnormal result of each NP test decreased significantly after 6 months of zinc administration (NCT-A, P < 0.001; NCT-B, P < 0.01; DST, P = 0.02, McNemar s test). However, no significant change was observed in the control group (NCT-A, P = 0.71; NCT-B, P = 0.06; DST, P = 0.44, McNemar s test). Significant change in the mean numbers of abnormal NP tests was observed between the zinc and control groups (P = 0.04, ANOVA). Associations of HRQOL and clinical variables Univariate associations between clinical variables and each of the 6-month changes in the two summary scores of SF-36 (DPCS and DMCS) are analysed. In univariate analysis, zinc supplementation and blood ammonia level were significantly associated with DPCS (P = 0.02, and P = 0.04 respectively), whereas no significant variable was associated with DMCS. In multivariate analysis, zinc supplementation was the only factor that affected DPCS (P = 0.03), whereas no significant variable affected DMCS (Table 4). DISCUSSION In this study, zinc supplementation in addition to standard treatment clearly demonstrated improved liver function, HE, NP tests, and HRQOL especially PCS, in patients with decompensated liver cirrhosis. Several reports describe zinc supplementation improving psychometric performance with a reduction in blood 1086 Aliment Pharmacol Ther 2010; 32:
8 Clinical trial: oral zinc in hepatic encephalopathy Table 3 Changes in clinical and laboratory parameters at 6-month follow-up Control group Zinc group Variable Baseline 6 months Baseline 6 months Child-Pugh score * Modified Child-Pugh score * MELD score Ascites (present absent) Average of the HE grade * No. of HE episodes per patient * Total bilirubin (mg dl) Albumin (g dl) * Prothrombin time (%) Ammonia (lg dl) * Platelets ( 10 4 ll) Zinc (lg dl) * Zinc deficiency (present absent) * Fischer ratio NCT-A (s) * NCT-A (abnormal normal) * NCT-B (s) * NCT-B (abnormal normal) * DST (points) * DST (abnormal normal) * Mean numbers of abnormal NP tests * MELD, model for end-stage liver disease; HE, hepatic encephalopathy; NCT, number connection test; DST, digit symbol test. Modified Child-Pugh score, qualitative HE assessment was excluded from Child-Pugh score (a range of 4 12). Values expressed as mean s.d. * Statistically significant, compared with each value prior to treatment, as determined via Student s paired t-test and McNemar s test. Statistically significant (P < 0.05), compared between zinc and control groups via ANOVA. ammonia level in HE patients. 10, 11 In addition, combinations of zinc and conventional therapies such as a protein-restricted diet including BCAA preparation or lactitol have been reported as effective therapies for HE. Hayashi et al. 28 reported that combination treatment with BCAA and zinc supplements decreased blood ammonia level more than BCAA treatment alone in cirrhotic patients during the study period. They inferred from this result that zinc administration increased ability to metabolize ammonia in the liver as compared with the nitrogen load by BCAA supplementation. Katayama 29 reported that while either lactitol or zinc alone reduced ammonia levels to about 70% of pre-treatment concentrations, combination treatment reduced them to about 50%. Synthetic disaccharides are effective in reducing blood ammonia by mainly inhibiting absorption of ammonia from the intestine, and are known to 30, 31 improve NP tests. This synergism of two agents for reducing ammonia caused by different mechanisms seems to be effective in patients unresponsive to standard therapies only. Zinc supplementation in addition to rifaximin, a minimally absorbed antibiotic, may be more effective in refractory HE, because a recent study 32 showed the superiority of rifaximin therapy over treatment with lactulose alone in severe recurrent HE patients. Our report is the first study confirming that zinc therapy is an effective treatment for HE patients who were Aliment Pharmacol Ther 2010; 32:
9 Y. Takuma et al. Dependent variable Independent variable Nonstandardized beta coefficient (95% CI) P value DPCS Zinc supplementation* 5.36 (0.47, 10.25) 0.03 Ammonia (lg dl) 5.78 ()0.80, 12.36) 0.08 DMCS Age (years) 0.26 ()0.044, 0.57) 0.09 Cause of cirrhosis (viral) )0.73 ()0.34, 9.05) 0.07 CI, confidence intervals; HE, hepatic encephalopathy; PCS, physical component scale; MCS, mental component scale; DPCS, change in PCS between two visits; DMCS, change in MCS between two visits. The clinical variables were considered either continuous or binary variables. Multivariate analysis; P values of stepwise backward multiple linear regression analysis are reported. * Significant (P < 0.05). Table 4 Predictors of change in PCS and MCS (n = 77) unresponsive to standard therapies in terms of improving patient HRQOL. In this study, zinc supplementation improved not only NP test results, but also the HRQOL in patients with HE. These results indicated that improvement in HRQOL was linked to improvement in cognitive functions. Moreover, in multivariate analysis, zinc supplementation was significantly associated with improvement in PCS, whereas zinc supplementation was not significantly associated with change in MCS. There are two possible explanations for these results. The first is improvement of physical manifestations in HE patients via zinc supplementation. Physical manifestations in HE patients presumably were tremor, ataxia, asterixis and ascites; consequently, improvements in these manifestations via zinc supplementation might correlate with change in PCS. Another possible explanation is difficulties in measurement of the mental component of mild HE patients via SF-36. Impairment of concentration such as shortened attention span or arithmetic disturbance is a main symptom in Grade 1 HE. Although improvement in concentration may improve the mental aspect, the SF-36 mental component appears to focus on energy rather than concentration, and this may explain the reason that the mental scale does not change. Hepatic encephalopathy, ascites, and Child-Pugh score have been known as variables associated with HRQOL in 24, 33, 34 patients with decompensated liver cirrhosis. In particular, HE and Child-Pugh score negatively correlated with physical health more than mental health in the SF , The results of zinc supplementation in this study were explanatory to the results of these reports. In this study, serum albumin level significantly increased, and the rate of ascites presence showed a tendency to decrease in the zinc group. BCAA recovers the impaired turnover kinetics of albumin in cirrhotic patients; 37 particularly, leucine is known to activate in vitro albumin synthesis through the mammalian target rapamycin (m-tor). 38 Reduction in BCAA in advanced liver cirrhosis was explained by enhanced consumption of BCAA for ammonia detoxification in skeletal muscle and for energy generation. Zinc supplementation enhanced ammonia detoxification in the liver, and consequently led to the alleviation of ammonia disposal in skeletal muscle. For this reason, zinc supplementation might result in a decrease of muscular BCAA consumption and consequently, the administered BCAA might be used for albumin synthesis, and lead to an increase in serum albumin level and a decrease in ascites. In this study, the Fischer ratio did not increase in the zinc group in spite of putative decrease in BCAA consumption, indicating the possibility of utilization of BCAA to synthesize albumin. The Child-Pugh score, the modified Child-Pugh score and mean HE grade improved, and serum albumin level increased by zinc supplementation. However, no significant change was observed in MELD score. Complications and laboratory parameters such as HE and ascites, and serum albumin are included in the Child-Pugh score, while HE and ascites are not part of the MELD score. For this reason, the Child-Pugh score correlates better with HRQOL than the MELD score. 35 It is necessary to understand the impact of liver disease on HRQOL because of the prolonged wait for transplantation. This result indicates that careful attention is required for patients awaiting transplant with advanced cirrhosis, 1088 Aliment Pharmacol Ther 2010; 32:
10 Clinical trial: oral zinc in hepatic encephalopathy because the authors found a poor correlation between HRQOL and MELD scores. There are several reports describing that plasma zinc concentrations of cirrhotic patients return to normal after treatment with mg per day of zinc sulphate or 600 mg per day of zinc acetate. 10, 11, 28 In spite of the small zinc dose (51 mg per day), the polaprezinc supplementation increased serum zinc level significantly in this study. Polaprezinc, a synthesized agent N-(3-aminopropionyl)-L-histidinate zinc, is a chelate compound consisting of zinc and L-carnosine, used clinically as an anti-pepticulcer drug. 39 L-carnosine enhances a strong zinc absorption from the intestine in animal models, 40 and 150 mg of polaprezinc (containing 34 mg of zinc per day) sustained human serum zinc levels higher than those of the 300 mg of zinc sulphate. 41 Limitations of this study are that it was conducted in a short period and non-blinded fashion; furthermore, it was assessed via nondisease-specific instruments. Although treatment bias is unavoidable, it may be minimal because this study was objectively assessed by the same scorer unaware of the assignment, via a battery of validated NP tests and relevant instrument of the SF-36 questionnaire. In spite of a generic instrument of the SF- 36, effectiveness in HRQOL after zinc therapy was confirmed. A disease-specific instrument such as the Chronic Liver Disease Questionnaire (CLDQ) 42 may be more reliable to measure the HRQOL in cirrhotic patients; however, most of the data using CLDQ have been derived from non-japanese patients; as such, little data for Japanese patients are available. A generic SF-36 is most widely used and valid in Japanese populations. Accordingly, SF-36 was adopted in this study. Several studies 43, 44 concluded that zinc supplementation failed to improve HE. The different outcome between those studies and the present one may be due to the difference in zinc supplementation period or background of participants. In conclusion, zinc supplementation may be an effective treatment for HE in terms of improving patient HRQOL. Prospective double-blind studies with large samples are necessary. ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Butterworth RF. Pathogenesis and treatment of portal-systemic encephalopathy: an update. Dig Dis Sci 1992; 37: Wein C, Koch H, Popp B, Oehler G, Schauder P. Minimal hepatic encephalopathy impairs fitness to drive. Hepatology 2004; 39: Conn HBJ. Hepatic Encephalopathy: Syndromes and Therapies. Bloomington, Illinois: Medi-Ed Press, Prasad S, Dhiman RK, Duseja A, et al. Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. Hepatology 2007; 45: Marchesini G, Bianchi G, Merli M, et al. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double blind, randomized trial. Gastroenterology 2003; 124: Muto Y, Sato S, Watanabe A, et al. Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clin Gastroenterol Hepatol 2005; 3: Hayashi M, Ohnishi H, Kawade Y, Muto Y, Takahashi Y. Augmented utilization of branched-chain amino acids by skeletal muscle in decompensated liver cirrhosis in special relation to ammonia detoxication. Gastroenterol Jpn 1981; 16: Horst D, Grace ND, Conn HO, et al. Comparison of dietary protein with an oral, branched chain-enriched amino acid supplement in chronic portal-systemic encephalopathy: a randomized controlled trial. Hepatology 1984; 4: Van der Rijt CC, Schalm SW, Schat H, Foeken K, De Jong G. Overt hepatic encephalopathy precipitated by zinc deficiency. Gastroenterology 1991; 100: Marchesini G, Fabbri A, Bianchi G, Brizi M, Zoli M. Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis. Hepatology 1996; 23: Reding P, Duchateau J, Bataille C. Oral zinc supplementation improves hepatic encephalopathy. Results of a randomised controlled trial. Lancet 1984; 2: Grüngreiff K, Presser HJ, Franke D, et al. Correlations between zinc, amino acids and ammonia in liver cirrhosis. Z Gastroenterol 1989; 27: Dejong CH, Deutz NE, Soeters PB. Muscle ammonia and glutamine exchange during chronic liver insufficiency in the rat. J Hepatol 1994; 21: Rabbani P, Prasad A. Plasma ammonia and liver ornithine transcarbamoylase activity in zinc-deficient rats. Am J Physiol 1978; 235: E Yoshida Y, Higashi T, Nouso K, et al. Effects of zinc deficiency zinc supplementation on ammonia metabolism in patients with decompensated liver cirrhosis. Acta Med Okayama 2001; 55: Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334: Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, Hepatology 2002; 35: Conn HO, Leevy CM, Vlahcevic ZR, et al. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology 1977; 72: Aliment Pharmacol Ther 2010; 32:
11 Y. Takuma et al. 19. Conn HO. Trailmaking and numberconnection tests in the assessment of mental state in portal systemic encephalopathy. Am J Dig Dis 1977; 22: Lezak MD. A compendium of tests and assessment techniques. In: Lezak MD, ed. Neuropsychological Assessment. New York: Oxford University Press, 1995: Kato A, Kato M, Ishii H, et al. Development of quantitative neuropsychological tests for diagnosis of subclinical hepatic encephalopathy in liver cirrhosis patients and establishment of diagnostic criteriamulticenter collaborative study in Japanese. Hepatol Res 2004; 30: Fukuhara S, Ware JE Jr, Kosinski M, Wada S, Gandek B. Psychometric and clinical tests of validity of the Japanese SF-36 Health Survey. J Clin Epidemiol 1998; 51: Fukuhara S, Bito S, Green J, Hsiao A, Kurokawa K. Translation, adaptation, and validation of the SF-36 Health Survey for use in Japan. J Clin Epidemiol 1998; 51: Marchesini G, Bianchi G, Amodio P, et al. Italian Study Group for quality of life incirrhosis. Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology 2001; 120: Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF- 36). Conceptual framework and item selection. Med Care 1992; 30: Ware JE Jr, Gandek B. Overview of the SF-36 Health Survey and the International Quality of Life Assessment (IQ- OLA) Project. J Clin Epidemiol 1998; 51: Dawson B, Trapp R. Basic and Clinical Biostatistics. 4th ed. USA: McGraw Hill, Hayashi M, Ikezawa K, Ono A, et al. Evaluation of the effects of combination therapy with branched-chain amino acid and zinc supplements on nitrogen metabolism in liver cirrhosis. Hepatol Res 2007; 37: Katayama K. Ammonia metabolism and hepatic encephalopathy. Hepatol Res 2004; 30S: Watanabe A, Sakai T, Sato S, et al. Clinical efficacy of lactulose in cirrhotic patients with and without subclinical hepatic encephalopathy. Hepatology 1997; 26: Dhiman RK, Sawhney MS, Chawla YK, et al. Efficacy of lactulose in cirrhotic patients with subclinical hepatic encephalopathy. Dig Dis Sci 2000; 45: Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362: Arguedas MR, DeLawrence TG, McGuire BM. Influence of hepatic encephalopathy on health-related quality of life in patients with cirrhosis. Dig Dis Sci 2003; 48: Younossi ZM, Boparai N, Price LL, et al. Health-related quality of life in chronic liver disease: the impact of type and severity of disease. Am J Gastroenterol 2001; 96: Saab S, Ibrahim AB, Shpaner A, et al. MELD fails to measure quality of life in liver transplant candidates. Liver Transpl 2005; 11: Kalaitzakis E, Josefsson A, Bjornsson E. Type and etiology of liver cirrhosis are not related to the presence of hepatic encephalopathy or health-related quality of life: a cross-sectional study. BMC Gastroenterol 2008; 8: Moriwaki H, Miwa Y, Tajika M, et al. Branched-chain amino acids as a protein- and energy-source in liver cirrhosis. Biochem Biophys Res Commun 2004; 313: Hara K, Yonezawa K, Weng QP, et al. Amino acid sufficiency and mtor regulate p70 S6 kinase and eif-4e BP1 through a common effector mechanism. J Biol Chem 1998; 273: Sano H, Furuta S, Toyama S, et al. Study on the metabolic fate of catena-(s)-[mu-[n alpha-(3-aminopropionyl)histidinato(2-)-n1,n2,o:n tau]- zinc]. 1st communication:absorption, distribution, metabolism and excretion after single administration to rats. Arzneimittelforschung 1991; 41: Nishimura Y, Yamagishi Y, Ando K, Saito T, Matsukura T. L-Carnosine and close derivatives accelerate zinc uptake from the intestine in rats. Biomedical Res Trace Elements 2001; 12: Nagamine T, Takagi H, Takayama H, et al. Preliminary study of combination therapy with interferon-a and zinc in chronic hepatitis C patients with genotype 1b. Biol Trace Elem Res 2000; 75: Younossi ZM, Grryatt G, Kiwi M, Moparai N, King D. Development of a disease-specific questionnaire to measure health related quality of life in patients with chronic liver disease. Gut 1999; 45: Riggio O, Ariosto F, Merli M, et al. Short-term oral zinc supplementation does not improve chronic hepatic encephalopathy. Results of a doubleblind crossover trial. Dig Dis Sci 1991; 36: Bresci G, Parisi G, Banti S. Management of hepatic encephalopathy with oral zinc supplementation: a long-term treatment. Eur J Med 1993; 2: Aliment Pharmacol Ther 2010; 32:
Oral Zinc Supplementation as an Adjunct Therapy in the Management of Hepatic Encephalopathy: A Randomized Controlled Trial
Oral Zinc Supplementation as an Adjunct Therapy in the Management of Hepatic Encephalopathy: A Randomized Controlled Trial Marcus R. Pereira A. Study Purpose Hepatic encephalopathy is a common complication
More informationrifaximin 550mg film-coated tablets (Targaxan ) SMC No. (893/13) Norgine Pharmaceuticals Ltd
rifaximin 550mg film-coated tablets (Targaxan ) SMC No. (893/13) Norgine Pharmaceuticals Ltd 09 August 2013 The Scottish Medicines Consortium (SMC) has completed its assessment of the above product and
More informationHepatic Encephalopathy, Hyperammonemia, and Current Treatment in ICU Room
Hepatic Encephalopathy, Hyperammonemia, and Current Treatment in ICU Room Assoc.Prof. Chan Sovandy Chairman by : Prof.So Saphy and Assoc Prof, Kim chhoung Hepatic Encephalopathy Hepatic (portal systemic
More information{ Rifaximin versus Nonabsorbable Disaccharides for the Treatment of Hepatic Encephalopathy: A Meta Analysis}
{ Rifaximin versus Nonabsorbable Disaccharides for the Treatment of Hepatic Encephalopathy: A Meta Analysis} {Dong Wu, Shu-Mei Wu, Jie Lu, Ying-Qun Zhou, Ling Xu, and Chuan-Yong Guo} Noor Al-Hakami, Pharm
More informationEvaluation and Prognosis of Patients with Cirrhosis
Evaluation and Prognosis of Patients with Cirrhosis Marion G. Peters, MD John V. Carbone, MD, Endowed Chair Professor of Medicine Chief of Hepatology Research University of California San Francisco Recorded
More informationAfter the Cure: Long-Term Management of HCV Liver Disease Norah A. Terrault, MD, MPH
After the Cure: Long-Term Management of HCV Liver Disease Norah A. Terrault, MD, MPH Professor of Medicine Department of Gastroenterology Director, Viral Hepatitis Center University of California San Francisco
More informationDIETARY THERAPY IMPACT FOR CIRRHOTIC PATIENTS WITH HEPATIC ENCEPHALOPATHY
ORIGINAL PAPER 373 DIETARY THERAPY IMPACT FOR CIRRHOTIC PATIENTS WITH HEPATIC ENCEPHALOPATHY Adriana Teiuşanu 1,, Mirela Ionescu 1, S. Gologan 1, Adriana Stoicescu 1, M. Andrei 1, T. Nicolaie 1, M. Diculescu
More informationPresented by: Jean Yoo-Campbell, Matthew Konerman, Monica Konerman, Jean Yoo Campbell, Christian Gocke, Eunpi Cho Donald Lynch
Bass N.M., et. al. N Engl J Med 2010; 362:1071-1081 Presented by: Jean Yoo-Campbell, Matthew Konerman, Monica Konerman, Jean Yoo Campbell, Christian Gocke, Eunpi Cho Donald Lynch Faculty Advisor: Dr. Fred
More informationDate of preparation: March 2015. GL/XIF/0214/0011a(1)
Date of preparation: March 2015. GL/XIF/0214/0011a(1) 1 This educational programme is funded by a grant from Norgine. Norgine has no involvement in the development of the content, which is developed independently
More informationThe pathogenesis of hepatic encephalopathy in
Correlation between Ammonia Levels and the Severity of Hepatic Encephalopathy Janus P. Ong, MD, Anjana Aggarwal, MD, Derk Krieger, MD, Kirk A. Easley, MS, Matthew T. Karafa, MS, Frederick Van Lente, PhD,
More informationCirrhosis and HCV. Jonathan Israel M.D.
Cirrhosis and HCV Jonathan Israel M.D. Outline Relationship of fibrosis and cirrhosisprevalence and epidemiology. Sequelae of cirrhosis Diagnosis of cirrhosis Effect of cirrhosis on efficacy of treatment
More informationEconomic Impact of Treatment Options for Hepatic Encephalopathy
Economic Impact of Treatment Options for Hepatic Encephalopathy Carroll B. Leevy, M.D. 1 ABSTRACT Complications of chronic liver disease, such as hepatic encephalopathy (HE), can have a substantial impact
More informationStudy of Effects of Probiotic Lactobacilli in Preventing Major Complications in Patients of Liver Cirrhosis
Research Article Study of Effects of Probiotic Lactobacilli in Preventing Major Complications in Patients of Liver Cirrhosis RR. Pawar*, ML. Pardeshi and BB. Ghongane Department of Pharmacology, B.J. Medical
More informationA systematic review and meta-analysis of the use of oral zinc in the treatment of hepatic encephalopathy
Chavez-Tapia et al. Nutrition Journal 2013, 12:74 REVIEW Open Access A systematic review and meta-analysis of the use of oral zinc in the treatment of hepatic encephalopathy Norberto C Chavez-Tapia 1*,
More informationPatterns of abnormal LFTs and their differential diagnosis
Patterns of abnormal LFTs and their differential diagnosis Professor Matthew Cramp South West Liver Unit and Peninsula Schools of Medicine and Dentistry, Plymouth Summary liver function / liver function
More informationDeveloping Innovative Therapeutics for People with Orphan Liver Disease
Developing Innovative Therapeutics for People with Orphan Liver Disease PIPELINE PROGRESS AND FIRST QUARTER 2015 EARNINGS UPDATE NASDAQ: OCRX Forward-Looking Statements Certain statements in this presentation
More informationHEPATIC ENCEPHALOPATHY; PRECIPITATING FACTORS IN PATIENTS WITH CIRRHOSIS
HEPATIC ENCEPHALOPATHY 375 ORIGINAL PROF-335 HEPATIC ENCEPHALOPATHY; PRECIPITATING FACTORS IN PATIENTS WITH CIRRHOSIS COL. DR. MANZAR ZAKARIA Classified Medical Specialist Department of Medicine DR. SYED
More informationSurveillance for Hepatocellular Carcinoma
Surveillance for Hepatocellular Carcinoma Marion G. Peters, MD John V. Carbone, MD, Endowed Chair Professor of Medicine Chief of Hepatology Research University of California San Francisco Recorded on April
More informationThe Multidimensional Burden of Hepatic Encephalopathy
The Multidimensional Burden of Project ID: 11-0014-NL-5 Credit Designation In the United States, chronic liver disease (CLD) is one of the leading causes of morbidity and mortality and affects approximately
More informationManagement of hepatitis C: pre- and post-liver transplantation. Piyawat Komolmit Bangkok
Management of hepatitis C: pre- and post-liver transplantation Piyawat Komolmit Bangkok Liver transplantation and CHC Cirrhosis secondary to HCV is the leading cause of liver transplantation in the US
More informationNP/PA Clinical Hepatology Fellowship Summary of Year-Long Curriculum
OVERVIEW OF THE FELLOWSHIP The goal of the AASLD NP/PA Fellowship is to provide a 1-year postgraduate hepatology training program for nurse practitioners and physician assistants in a clinical outpatient
More informationMANAGEMENT OF LIVER CIRRHOSIS
MANAGEMENT OF LIVER CIRRHOSIS Information Leaflet Your Health. Our Priority. Page 2 of 6 What is cirrhosis? Cirrhosis is a result of long-term, continuous damage to the liver and may be due to many different
More informationLiver Transplantation for Hepatocellular Carcinoma. John P. Roberts, MD Chief, Division of Transplant Service University of California, San Francisco
Liver Transplantation for Hepatocellular Carcinoma John P. Roberts, MD Chief, Division of Transplant Service University of California, San Francisco Hepatocellular Carcinoma HCC is the 5th most common
More informationPrecipitating Factors of Hepatic Encephalopathy
Original Article Precipitating Factors of Hepatic Encephalopathy Mohammad Tariq,* Saleem Iqbal,** Naji ullah Khan,* Rabia Basri*** From Department of Medicine, Khyber Teaching Hospital, Peshawar. *Post
More informationHuman Clinical Study for Free Testosterone & Muscle Mass Boosting
Human Clinical Study for Free Testosterone & Muscle Mass Boosting GE Nutrients, Inc. 920 E. Orangethorpe Avenue, Suite B Anaheim, California 92801, USA Phone: +1-714-870-8723 Fax: +1-732-875-0306 Contact
More informationDrugs for MS.Drug fact box cannabis extract (Sativex) Version 1.0 Author
Version History Policy Title Drugs for MS.Drug fact box cannabis extract (Sativex) Version 1.0 Author West Midlands Commissioning Support Unit Publication Date Jan 2013 Review Date Supersedes/New (Further
More informationBURDEN OF LIVER DISEASE IN BRAZIL
BURDEN OF LIVER DISEASE IN BRAZIL Burden of Liver Disease in Europe Blachier et al. J Hepatol 58:593, 2013 Review of 260 epidemiologic studies of the 5 previous years Cirrhosis is responsible for 170.000
More informationLamivudine for Patients with hronic Hepatitis B and Advanced Liver Disease. From : New England Journal of Medicine
Lamivudine for Patients with hronic Hepatitis B and Advanced Liver Disease From : New England Journal of Medicine Volume 351:1521-1531, Number 15, Oct 7, 2004 馬 偕 紀 念 醫 院 一 般 內 科, 肝 膽 腸 胃 科 新 竹 分 院 陳 重
More informationDietary treatment of cachexia challenges of nutritional research in cancer patients
Dietary treatment of cachexia challenges of nutritional research in cancer patients Trude R. Balstad 4th International Seminar of the PRC and EAPC RN, Amsterdam 2014 Outline Cancer cachexia Dietary treatment
More informationABSTRACT INTRODUCTION. Roxana Irimia 1, Carol Stanciu 2, Camelia Cojocariu 1,2, Cătălin Sfarti 1,2, Anca Trifan 1,2
Oral Glutamine Challenge Improves the Performance of Psychometric Tests for the Diagnosis of Minimal Hepatic Encephalopathy in Patients with Liver Cirrhosis Roxana Irimia 1, Carol Stanciu 2, Camelia Cojocariu
More informationLIVER TRANSPLANTATION IN ALAGILLE SYNDROME
LIVER TRANSPLANTATION IN ALAGILLE SYNDROME Ronald J. Sokol, MD Children s Hospital Colorado University of Colorado School of Medicine Treatment of Liver Disease in Improve bile flow ALGS Ursodeoxycholic
More informationClinical Study Synopsis
Clinical Study Synopsis This file is posted on the Bayer HealthCare Clinical Trials Registry and Results website. It is provided for patients and healthcare professionals to increase the transparency of
More informationCOMPLICATIONS OF CIRRHOSIS COMPLICATIONS OF CIRRHOSIS OBSERVATIONS OF AN AGING HEPATOLOGIST. Philip C. Delich, M.D.
1 COMPLICATIONS OF CIRRHOSIS OBSERVATIONS OF AN AGING HEPATOLOGIST COMPLICATIONS OF CIRRHOSIS Philip C. Delich, M.D. Faculty Disclosure Dr. Delich has indicated that he does not have any relevant financial
More informationSBRT (Elekta), 45 Gy in fractions of 3 Gy 3x/week for 5 weeks (N=22) vs.
Uitgangsvraag 6: Wat is de plaats van stereotactische radiotherapiebehandeling (SBRT) bij HCC patiënten? Primaire studies I Study ID II Method III Patient characteristics IV Intervention(s) V Results primary
More informationBranched-chain amino acids for people with hepatic encephalopathy (Review)
Branched-chain amino acids for people with hepatic encephalopathy (Review) Gluud LL, Dam G, Les I, Córdoba J, Marchesini G, Borre M, Aagaard NK, Vilstrup H This is a reprint of a Cochrane review, prepared
More informationPREVENTION OF HCC BY HEPATITIS C TREATMENT. Morris Sherman University of Toronto
PREVENTION OF HCC BY HEPATITIS C TREATMENT Morris Sherman University of Toronto Pathogenesis of HCC in chronic hepatitis C Injury cirrhosis HCC Injury cirrhosis HCC Time The Ideal Study Prospective randomized
More informationNUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #95. Hepatic Encephalopathy: Are NH 4 Levels and Protein Restriction Obsolete?
Carol Rees Parrish, R.D., M.S., Series Editor Hepatic Encephalopathy: Are NH 4 Levels and Protein Restriction Obsolete? Peter Caruana Neeral Shah Measurement of plasma ammonia and restriction of dietary
More informationIf several different trials are mentioned in one publication, the data of each should be extracted in a separate data extraction form.
General Remarks This template of a data extraction form is intended to help you to start developing your own data extraction form, it certainly has to be adapted to your specific question. Delete unnecessary
More informationGT-020 Phase 1 Clinical Trial: Results of Second Cohort
GT-020 Phase 1 Clinical Trial: Results of Second Cohort July 29, 2014 NASDAQ: GALT www.galectintherapeutics.com 2014 Galectin Therapeutics inc. Forward-Looking Statement This presentation contains, in
More informationEnd Stage Liver Disease: What is New? Marion Peters MD UCSF Berlin 2012
End Stage Liver Disease: What is New? Marion Peters MD UCSF Berlin 2012 Natural History of ESLD Increasing liver fibrosis Development of HCC Chronic liver disease Compensated cirrhosis Decompensated cirrhosis
More informationHEPATIC ENCEPHALOPATHY
HEPATIC ENCEPHALOPATHY Jan Albrecht Department of Neurotoxicology, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland Brussels, July 14, 2009 DEFINITIONS: - HEPATIC ENCEPHALOPATHY (HE)
More informationGENERAL INFORMATION. Adverse Event (AE) Definition (ICH GUIDELINES E6 FOR GCP 1.2):
Make copies of the blank SAE report form as needed. Retain originals with confirmation of all information faxed to DMID Pharmacovigilance Group Clinical Research Operations and Management Support (CROMS
More informationPEER REVIEW HISTORY ARTICLE DETAILS VERSION 1 - REVIEW
PEER REVIEW HISTORY BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form (http://bmjopen.bmj.com/site/about/resources/checklist.pdf)
More informationNUTRITION IN LIVER DISEASES
NUTRITION IN LIVER DISEASES 1. HEPATITIS: Definition: - Viral inflammation of liver cells. Types: a. HAV& HEV, transmitted by fecal-oral route. b. HBV & HCV, transmitted by blood and body fluids. c. HDV
More informationReview Group: Mental Health Operational Medicines Management Group. Signature Signature Signature. Review Date: December 2014
Mental Health NHS Grampian Mental Health Service Staff Guidance For The Prescribing Of Vitamin Supplementation During In-Patient Admission (Mental Health) For Alcohol Withdrawal Co-ordinators: Consultant
More informationThe State of the Liver in the Adult Patient after Fontan Palliation
The State of the Liver in the Adult Patient after Fontan Palliation Fred Wu, M.D. Boston Adult Congenital Heart Service Boston Children s Hospital/Brigham & Women s Hospital 7 th National Adult Congenital
More informationDVT/PE Management with Rivaroxaban (Xarelto)
DVT/PE Management with Rivaroxaban (Xarelto) Rivaroxaban is FDA approved for the acute treatment of DVT and PE and reduction in risk of recurrence of DVT and PE. FDA approved indications: Non valvular
More informationThe following should be current within the past 6 months:
EVALUATION Baseline Labs Obtain at time or prior to initial evaluation CBC with diff PT/INR CMP HCV Genotype (obtained PRIOR TO consult visit) HCV RNA (obtained PRIOR TO consult visit) Hep A IgG Hep BsAg,
More informationboceprevir 200mg capsule (Victrelis ) Treatment naïve patients SMC No. (723/11) Merck Sharpe and Dohme Ltd
boceprevir 200mg capsule (Victrelis ) Treatment naïve patients SMC No. (723/11) Merck Sharpe and Dohme Ltd 09 September 2011 The Scottish Medicines Consortium (SMC) has completed its assessment of the
More informationNot All Clinical Trials Are Created Equal Understanding the Different Phases
Not All Clinical Trials Are Created Equal Understanding the Different Phases This chapter will help you understand the differences between the various clinical trial phases and how these differences impact
More informationAlcoholic Hepatitis (Teacher s Guide)
Thomas Ormiston, M.D. Updated 5/5/15 2007-2015, SCVMC Alcoholic Hepatitis (Teacher s Guide) (30 minutes) I. Objectives Recognize the signs and symptoms of alcoholic hepatitis Understand the treatment options
More informationA 55 year old man with cirrhosis due to chronic hepatitis C (CHC) genotype 3a is referred for liver transplantation.
A 55 year old man with cirrhosis due to chronic hepatitis C (CHC) genotype 3a is referred for liver transplantation. Three years ago he was treated with 24 weeks of peginterferon alfa-2a (180 µg/wk, PEGIFN)
More informationplacebo-controlledcontrolled double-blind, blind,
Clinical Potential of Minocycline for Depression with Psychotic Features Tsuyoshi Miyaoka Department of Psychiatry Shimane University School of Medicine Minocycline 1. Second-generation tetracycline which
More informationboceprevir 200mg capsule (Victrelis ) Treatment experienced patients SMC No. (722/11) Merck, Sharpe and Dohme Ltd
boceprevir 200mg capsule (Victrelis ) Treatment experienced patients SMC No. (722/11) Merck, Sharpe and Dohme Ltd 09 September 2011 The Scottish Medicines Consortium (SMC) has completed its assessment
More informationObjective: To investigate the hepatic clearance of NRL972 in patients undergoing alcohol withdrawal therapy
Title of the Study: A multi-centre, open, short term follow-up Phase II study to evaluate the clearance of NRL972 in patients undergoing alcohol withdrawal commencing in a controlled clinical setting Short
More informationMaintenance of abstinence in alcohol dependence
Shared Care Guideline for Prescription and monitoring of Acamprosate Calcium Author(s)/Originator(s): (please state author name and department) Dr Daly - Consultant Psychiatrist, Alcohol Services Dr Donnelly
More informationStudy Design and Statistical Analysis
Study Design and Statistical Analysis Anny H Xiang, PhD Department of Preventive Medicine University of Southern California Outline Designing Clinical Research Studies Statistical Data Analysis Designing
More informationLIVER FUNCTION TESTS AND STATINS
LIVER FUNCTION TESTS AND STATINS Philippe J. Zamor and Mark W. Russo Current Opinion in Cardiology 2011,26:338 341 SUMMARY Purpose of review: To discuss recent data on statins in patients with elevated
More informationClinical Trial Design. Sponsored by Center for Cancer Research National Cancer Institute
Clinical Trial Design Sponsored by Center for Cancer Research National Cancer Institute Overview Clinical research is research conducted on human beings (or on material of human origin such as tissues,
More informationSystolic Blood Pressure Intervention Trial (SPRINT) Principal Results
Systolic Blood Pressure Intervention Trial (SPRINT) Principal Results Paul K. Whelton, MB, MD, MSc Chair, SPRINT Steering Committee Tulane University School of Public Health and Tropical Medicine, and
More informationHepatitis C Treatment Criteria Commercial & Minnesota Health Care Programs
Last update: February 23, 2015 Hepatitis C Treatment Criteria Commercial & Minnesota Health Care Programs Please see healthpartners.com for Medicare coverage criteria. Table of Contents 1. Harvoni 2. Sovaldi
More informationLactulose for Minimal Hepatic Encephalopathy in Patients with Extrahepatic Portal Vein Obstruction
Original Article Lactulose for Minimal Hepatic Encephalopathy in Patients with Extrahepatic Portal Vein Obstruction Praveen Sharma, Barjesh Chander Sharma Department of, G. B. Pant Hospital, New Delhi,
More informationJune 11, 2015 Tim Halterman
June 11, 2015 Tim Halterman Defini&on Histologic change + loss of liver function Derives from Greek word kirrhos meaning yellow, tawny First named by Rene Laennec in 1819 Laennec s cirrhosis=alcoholic
More informationHepatitis C Virus Direct-Acting Antivirals Prior Authorization Request Form
Hepatitis C Virus Direct-Acting Antivirals Prior Authorization Request Form For assistance, please call 1-855-552-6028 or fax completed form to 570-271-5610. Medical documentation may be requested. This
More informationNutrition in Liver Disease
Nutrition in Liver Disease Mathias Plauth Klinik für Innere Medizin Städtisches Klinikum Dessau Nestlé 10 th Clinical Nutrition Course June 5-10, 2011, Lausanne, Switzerland Malnutrition in Cirrhosis?
More informationTherapy of decompensated cirrhosis Pre-transplant for HBV and HCV
Therapy of decompensated cirrhosis Pre-transplant for HBV and HCV Universitätsklinikum Leipzig Thomas Berg Sektion Hepatologie Klinik und Poliklinik für Gastroenterologie und Rheumatologie Leber- und Studienzentrum
More informationA CASE OF LIVER CIRRHOSIS & HEPATIC ENCEPHALOPATHY
A CASE OF LIVER CIRRHOSIS & HEPATIC ENCEPHALOPATHY 2 1 Mr N.N. 56 yr old male. Admitted on 22/03/02. 1 month Hx of abdominal distention, confusion, inability to concentrate and dyspnoea Grade 111. Pmx:
More informationHEPATOCELLULAR CARCINOMA (HCC) RESECTION VERSUS TRANSPLANTATION. Francis Yao, M.D.
UCSF TRANSPLANT CONFERENCE - 9/28/2012 HEPATOCELLULAR CARCINOMA (HCC) RESECTION VERSUS TRANSPLANTATION Francis Yao, M.D. Professor of Clinical Medicine and Surgery Medical Director, Liver Transplantation
More informationAcute alcohol withdrawal
A NICE pathway brings together all NICE guidance, quality standards and materials to support implementation on a specific topic area. The pathways are interactive and designed to be used online. This pdf
More informationGuidance for Industry
Guidance for Industry Cancer Drug and Biological Products Clinical Data in Marketing Applications U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and
More informationApproach to Abnormal Liver Tests
Approach to Abnormal Liver Tests Naga P. Chalasani, MD, FACG Professor of Medicine and Cellular & Integrative Physiology Director, Division of Gastroenterology and Hepatology Indiana University School
More informationThe Role of Probiotic in Patient with Minimal Hepatic Encephalopathy: An Evidence Based Case Report
The Role of Probiotic in Patient with Minimal Hepatic Encephalopathy: An Evidence Based Case Report Author dr. M. Adi Firmansyah NPM: 0806484692 Supervisor dr. Andri S. Sulaiman, SpPD-KGEH Department of
More informationPRIOR AUTHORIZATION PROTOCOL FOR HEPATITIS C TREATMENT
PRIOR AUTHORIZATION PROTOCOL FOR HEPATITIS C TREATMENT HARVONI (90mg ledipasvir/400mg sofosbuvir): tablet (PREFERRED AGENT) SOVALDI (sofosbuvir ): 400mg tablets (PREFERRED AGENT ) OLYSIO (simeprivir) PEG-INTRON
More informationRole of Branched Chain Amino Acids in the Management of Hepatic Encephalopathy
World Journal of Medical Sciences 3 (2): 60-64, 2008 ISSN 1817-3055 IDOSI Publications, 2008 Role of Branched Chain Amino Acids in e Management of Hepatic Encephalopay 1 1 1 1 2 Aftab Ahmed Soomro, Bikha
More informationClinical Study Synopsis
Clinical Study Synopsis This Clinical Study Synopsis is provided for patients and healthcare professionals to increase the transparency of Bayer's clinical research. This document is not intended to replace
More informationPrior Authorization Guideline
Prior Authorization Guideline Guideline: PDP IBT Inj - Vivitrol Therapeutic Class: Central Nervous System Agents Therapeutic Sub-Class: Opiate Antagonist Client: 2007 PDP IBT Inj Approval Date: 2/20/2007
More informationHepatocellular Carcinoma Treatment Decision Tree
Treatment Decision Tree Derek DuBay, MD Assistant Professor of Surgery Liver Transplant and Hepatobiliary Surgery UAB Department of Surgery 1 UAB Liver Tumor Clinic Referrals: 205 996 5970 (phone) 205
More informationOmega-3 fatty acids improve the diagnosis-related clinical outcome. Critical Care Medicine April 2006;34(4):972-9
Omega-3 fatty acids improve the diagnosis-related clinical outcome 1 Critical Care Medicine April 2006;34(4):972-9 Volume 34(4), April 2006, pp 972-979 Heller, Axel R. MD, PhD; Rössler, Susann; Litz, Rainer
More informationLiver Diseases. An Essential Guide for Nurses and Health Care Professionals
Brochure More information from http://www.researchandmarkets.com/reports/1047385/ Liver Diseases. An Essential Guide for Nurses and Health Care Professionals Description: Liver disease is a rapidly growing
More informationRecommendations 8/14/2014. Hepatitis C Clinical Approach Primary Care. Purpose of Presentation. HCV Prevalence Year of Birth
Hepatitis C Clinical Approach Primary Care Dr. Vicki L. MIt McIntyre, FNP Tucson Gastroenterology Specialists Tucson, Arizona University of Phoenix Lead Faculty, Department of Nursing Tucson, Arizona Purpose
More informationClinical Study Synopsis
Clinical Study Synopsis This Clinical Study Synopsis is provided for patients and healthcare professionals to increase the transparency of Bayer's clinical research. This document is not intended to replace
More information3/25/2014. April 3, 2014. Dennison MM, et al. Ann Intern Med. 2014;160:293 300.
April 3, 2014 3.6 million persons ever infected; 2.7 million chronic infections 1 Up to 75% unaware of status Transmitted through percutaneous exposure to infected blood Injection drug use (IDU) is the
More informationWhat to Do with the Patient With Abnormal Liver Enzymes? Nizar N. Zein, M.D. The Cleveland Clinic
What to Do with the Patient With Abnormal Liver Enzymes? Nizar N. Zein, M.D. The Cleveland Clinic Introduction Elevated liver enzymes is often not a clinical problem by itself. However it is a warning
More informationDoes referral from an emergency department to an. alcohol treatment center reduce subsequent. emergency room visits in patients with alcohol
Does referral from an emergency department to an alcohol treatment center reduce subsequent emergency room visits in patients with alcohol intoxication? Robert Sapien, MD Department of Emergency Medicine
More informationTHE EFFECT OF SODIUM CHLORIDE ON THE GLUCOSE TOLERANCE OF THE DIABETIC RAT*
THE EFFECT OF SODIUM CHLORIDE ON THE GLUCOSE TOLERANCE OF THE DIABETIC RAT* BY JAMES M. ORTEN AND HENRY B. DEVLINt (From the Deparkment of Physiological Chemistry, Wayne University College of Medicine,
More informationProbiotic for the Treatment of Minimal Hepatic Encephalopathy: Preliminary Report ABSTRACT
Original Article Issariyakulkarn N, et al. THAI J GASTROENTEROL 2010 Vol. 11 No. 3 Sept. - Dec. 2010 129 Issariyakulkarn N Sanpajit T Surangsrirat S ABSTRACT Objectives: Minimal hepatic encephalopathy
More informationExamination Content Blueprint
Examination Content Blueprint Overview The material on NCCPA s certification and recertification exams can be organized in two dimensions: (1) organ systems and the diseases, disorders and medical assessments
More informationPROTOCOL SYNOPSIS Evaluation of long-term opioid efficacy for chronic pain
P a g e 1 PROTOCOL SYNOPSIS Evaluation of long-term opioid efficacy for chronic pain Clinical Phase 4 Study Centers Study Period 25 U.S. sites identified and reviewed by the Steering Committee and Contract
More informationAcute on Chronic Liver Failure: Current Concepts. Disclosures
Acute on Chronic Liver Failure: Current Concepts Vandana Khungar, MD MSc Assistant Professor of Medicine University of Pennsylvania, Perelman School of Medicine September 20, 2015 None to declare Disclosures
More informationLeading the Way to Treat Liver Cancer
Leading the Way to Treat Liver Cancer Guest Expert: Sukru, MD Professor of Transplant Surgery Mario Strazzabosco, MD Professor of Internal Medicine www.wnpr.org www.yalecancercenter.org Welcome to Yale
More informationUpdate and Review of Medication Assisted Treatments
Update and Review of Medication Assisted Treatments for Opiate and Alcohol Use Disorders Richard N. Whitney, MD Medical Director Addiction Services Shepherd Hill Newark, Ohio Medication Assisted Treatment
More informationPrior Authorization Policy
Prior Authorization Policy http://www.paramounthealthcare.com/providers Ribavirin Rebetol (ribavirin capsule or oral solution) Copegus (ribavirin tablet), Moderiba (ribavirin tablet), Ribasphere (ribavirin
More informationLedipasvir/Sofosbuvir (Harvoni) for Treatment of Hepatitis C
Ledipasvir/Sofosbuvir (Harvoni) for Treatment of Hepatitis C Policy Number: Original Effective Date: MM.04.034 12/1/2014 Line(s) of Business: Current Effective Date: HMO; PPO; QUEST Integration 12/1/2014
More informationHCV/HIVCo-infection A case study by. Dominic Côté, Nurse Clinician B.Sc Chronic Viral Illness Services McGill University Health Centre
HCV/HIVCo-infection A case study by Dominic Côté, Nurse Clinician B.Sc Chronic Viral Illness Services McGill University Health Centre Objectives By sharing a case study of a patient co-infected with HIV/HCV
More informationFREEDOM C: A 16-Week, International, Multicenter, Double-Blind, Randomized, Placebo-Controlled Comparison of the Efficacy and Safety of Oral UT-15C
FREEDOM C: A 16-Week, International, Multicenter, Double-Blind, Randomized, Placebo-Controlled Comparison of the Efficacy and Safety of Oral UT-15C SR in Combination with an ERA and/or a PDE-5 Inhibitor
More informationAntipsychotic drugs are the cornerstone of treatment
Article Effectiveness of Olanzapine, Quetiapine, Risperidone, and Ziprasidone in Patients With Chronic Schizophrenia Following Discontinuation of a Previous Atypical Antipsychotic T. Scott Stroup, M.D.,
More informationBACKGROUND MEDIA INFORMATION Fast facts about liver disease
BACKGROUND MEDIA INFORMATION Fast facts about liver disease Liver, or hepatic, disease comprises a wide range of complex conditions that affect the liver. Liver diseases are extremely costly in terms of
More informationNurse Practitioner Outcomes: The Integration & Future Directions of The Liver Transplant NP. Amanda Tinning MN NP October 13, 2011
Nurse Practitioner Outcomes: The Integration & Future Directions of The Liver Transplant NP Amanda Tinning MN NP October 13, 2011 Overview Define clinical outcomes Discuss the contributions of the NP role
More informationSponsor Novartis. Generic Drug Name Secukinumab. Therapeutic Area of Trial Psoriasis. Approved Indication investigational
Clinical Trial Results Database Page 2 Sponsor Novartis Generic Drug Name Secukinumab Therapeutic Area of Trial Psoriasis Approved Indication investigational Clinical Trial Results Database Page 3 Study
More informationINTOXICATED PATIENTS AND DETOXIFICATION
VAMC Detoxification Decision Tree Updated May 2006 INTOXICATED PATIENTS AND DETOXIFICATION Patients often present for evaluation of substance use and possible detoxification. There are certain decisions
More information