The choice of zinc in hepatic encephalopathy
- Categories:Stomach healthy
- Time of issue:2021-01-19
The choice of zinc in hepatic encephalopathy
- Categories:Stomach healthy
- Time of issue:2021-01-19
Hepatic encephalopathy (he) affects the quality of life of 20% - 30% of patients with liver cirrhosis. It can lead to the reversible decline of cognitive function and seriously affect the health-related quality of life (HRQOL) of patients. Improving cognitive function can improve HRQOL. HRQOL is the main index to evaluate the efficacy of he, because he is a poor prognostic factor in patients with liver cirrhosis. Studies have shown that ammonia level is the influencing factor of hepatic encephalopathy, and the decrease of blood ammonia level will affect he grading and improve the results of neuropsychological tests.
Synthetic disaccharides (lactulose and lactitol) are commonly used in the treatment of advanced liver cirrhosis. Studies have shown that lactulose improves the quality of life in patients with mild he; however, some patients do not respond to these drugs because it reduces ammonia absorption. Branched chain amino acids (BCAA) is another drug for the treatment of he. Studies have shown that it can significantly reduce the incidence of complications in patients with advanced liver cirrhosis. However, branched chain amino acids may increase blood ammonia levels in patients with protein intolerance.
Polyprezinc (PZ) is a chelate composed of zinc ions and L-carnosine. Zinc supplementation is another important choice for the treatment of he. Studies have shown that zinc supplementation can significantly improve he. Patients with cirrhosis and he often have zinc deficiency, which can lead to nitrogen metabolism disorder and hyperammonemia. Zinc supplementation can improve the ability of transforming amino acids into urea in liver, reduce the level of serum ammonia and improve the quality of life. The purpose of this study is to explore the benefits of zinc supplementation on the quality of life of patients with he.
1 test method
1.1 research design
The subjects in this study were randomly divided into two groups according to the ratio of 1:1. One group received standard protein restricted diet treatment of polyprazeb (225 mg), including branched chain amino acids (BCAA) and lactulose (zinc group), and the other group only received standard treatment (control group). The course of treatment was 6 months.
Polyprazeb is a granular drug, so it is very difficult to make placebo with similar taste and dose. Based on the above reasons, this study did not use blind method, but used computer-generated form to randomly divide the subjects into zinc group and control group. The minimization method was used to adjust the he classification and the imbalance between inpatients and outpatients between the two groups. Each group was blinded to the scorer (M.H.) and disclosed to the main researcher (Y.T.).
1.2 inclusion criteria
Inclusion criteria: patients who were histologically or clinically diagnosed as liver cirrhosis and taking BCAA at least 3 months before enrollment; patients with hyperammonemia; patients with grade 1 or 2 recurrent he, who did not respond to standard therapy, took 30-60ml lactulose and protein restricted diet every day for at least 4 weeks.
Exclusion criteria: Patients with hepatocellular carcinoma; patients with alcoholic liver cirrhosis who did not quit drinking at least one year before enrollment; severe complications of liver cirrhosis, including serum albumin concentration < 2.5G ／ DL, serum total bilirubin concentration ≥ 3.0mg ／ DL and recurrent he grade 3 or higher; patients who used antibiotics and drugs affecting psychological test; patients with history of gastrointestinal bleeding; patients with shunt history, transjugular vein hepatectomy The patients who had internal portosystemic shunt or retrograde veno venous occlusion with balloon occlusion, aged more than 80 years, had organic neurological diseases such as subdural hematoma, Wernicke's disease, encephalitis, other metabolic abnormalities and drug poisoning.
1.3 he score and quality of life evaluation
During the trial, the patients with obvious he attack were divided into inpatients and outpatients according to the severity of he attack. Outpatients were evaluated every other week. Recurrent he was defined as at least three times of dominant he within one month under the condition of continued use of lactulose and limited protein diet. The diagnosis and grading of overt he were based on clinical and neuropsychological abnormalities, using West Haven criteria, including state of consciousness, intellectual function, personality behavior and neuromuscular abnormalities. Finally, two hepatologists consulted a neurologist to determine the diagnosis and grading of he.
NCT and DST were used as neuropsychological tests of he. For nct-a, patients were asked to connect 1 to 20 numbers scattered on a page in the fastest possible order (time limit: 120s). For nct-b, patients were asked to connect numbers from 1 to 10 with 10 Japanese characters scattered on a page as soon as possible (time limit: 180s). Low scores indicate good performance. DST was included in the revised Wechsler Adult Intelligence Scale. The researchers gave the subjects a table of numbers from 1 to 9 and asked them to fill in the blanks with the symbols corresponding to each number. The test score is the total number of symbols matched in the correct order within the 60s interval (up to 40 questions). High scores indicate good performance.
The outliers of nct-a, nct-b and DST were determined according to the upper and lower 10 percentiles. The results were influenced by age, but not by gender, facilities or education. The main outcome measure was the change of physical health (PCS) in SF-36 second edition questionnaire within 6 months. PC was more likely to be affected by he than mental health. SF-36 was used to collect quality of life information in eight health areas. The score of each scale ranged from 0 to 100. The lower the score, the worse the health status or the greater the degree of disability. Two standardized total scores, PCs and MCS, were calculated from SF-36 raw data, which is helpful to evaluate the quality of life of patients with advanced liver disease. Secondary efficacy measures were changes in he classification, other clinical parameters, NP tests, and any symptoms included in adverse events within 6 months.
1.4 follow up
During the study period, the clinical evaluation and laboratory parameters, adverse events and compliance with the test drug of the two groups were evaluated every 1 month. An independent scorer assessed the subjects at baseline and 6 months through a series of NP tests and SF-36 questionnaires without knowing the grouping. All subjects received dietary assessment and recommendations from the study nutritionist at baseline and at 3 months. If there is at least one grade improvement in he score at the end of the study period, it is considered that there is a response. If there is deterioration or no change in he score at the end of the study period, it is considered that there is no response.
1.5 statistical analysis
In the randomized cohort, the sample size of 39 patients in each group was determined. Compared with the standard treatment, the PCs score of zinc treatment increased by 20%, α error was 5% (two tailed), β error was 80%. Mann Whitney U test, chi square test and Fisher exact test were used to analyze the differences of baseline data between the two groups. Spearman rank correlation was used to analyze the correlation between two total scores of SF-36 and continuous clinical parameters. Analysis of variance (ANOVA) was used to detect the correlation between the two total scores of SF-36 and clinical data. In order to explore the independent predictors of the six-month change of SF-36 total scores, all single variables were analyzed by stepwise reverse multiple linear regression, and the variables with P < 0.1 were retained in the multivariate model. Student paired t test was used to compare the serum values before and after treatment, and McNemar test was used to compare the abnormal rate of NP test before and after treatment. Analysis of variance was used to analyze the changes of clinical parameters between the two groups. The results were analyzed by intention to treat (ITT) population. P < 0.05, with statistical significance.
2 results and analysis
2.1 subject recruitment
During the study, 156 patients with cirrhosis were screened, and 79 (51%) met the inclusion criteria (Figure 1). Thirty nine patients with he received zinc supplementation on the basis of standard treatment, and 40 patients only received standard treatment for 6 months. The excluded reasons (77 cases, 49%) included refusal to participate (6 cases), advanced HCC (21 cases), complex chronic recurrent grade 3 or above (10 cases), recent gastrointestinal bleeding (10 cases), serum albumin concentration < 2.5g/dl (8 cases), serum total bilirubin concentration ≥ 3.0mg/dl (6 cases), recent drinking history (5 cases), recent use of antibiotics (5 cases), and recent use of antibiotics affecting mental health There were 3 cases of drugs for motor function, 2 cases of severe involuntary movement (such as tremor) not suitable for NP test, and 1 case of retrograde veno venous occlusion with balloon occlusion.
Figure 1 flow chart of subject recruitment
2.2 baseline characteristics
Clinical and demographic characteristics are shown in Table 1. Cirrhosis was caused by chronic viral hepatitis (58 cases), alcoholic liver injury (13 cases), primary biliary cirrhosis (3 cases), autoimmune hepatitis (2 cases) and cryptogenic cirrhosis (3 cases). There was no statistically significant difference in baseline characteristics between the zinc group and the control group. Zinc deficiency occurred in 38 cases (97%) of zinc group and 38 cases (95%) of control group (plasma zinc concentration < 70 μ g / dl). There was no significant difference between the groups in the baseline value of single field and the total score of SF-36 (Table 2).
Table 1 baseline characteristics of the two groups
Table 2 SF-36 and NP tests at baseline in two groups
2.3 benefits of zinc supplementation on patients' quality of life
Figure 2 shows the effect of zinc supplementation on SF-36. After 6 months, RP and PCs were significantly improved in zinc group (P = 0.04, P = 0.02), but there was no significant change in control group. Compared with the control group, PF, RP and PCs in zinc group were significantly improved (P = 0.04, P < 0.01, P = 0.04); however, compared with the control group, other variables were not significantly improved (P = 0.95).
Figure 2 changes in various fields (mean ± SD) and total scores of health-related quality of life (SF-36) in patients with liver cirrhosis randomly divided into control group (hollow group) and zinc group (solid group) after 6 months. *By student paired t-test, compared with each value before treatment, it had statistical significance (P < 0.05). The difference was statistically significant (P < 0.05). Abbreviations: PF, physical function; RP, role physiology; BP, physical pain; GH, general health; VT, vitality; SF, social function; re, role emotion; MH, mental health; PCs, physical health; MCS, mental health.
2.4 zinc supplementation reduces blood ammonia level
In the zinc group, child Pugh and modified child Pugh scores, mean he grade and mean he attack were significantly improved (P < 0.001, P = 0.02, P < 0.01, P < 0.0001), serum albumin and serum zinc levels were increased (P = 0.02, P < 0.0001), and blood ammonia level was decreased (P < 0.0001) (Table 3). In addition, the incidence of ascites in zinc group showed a downward trend (P = 0.08). There was no significant change in serum laboratory value in the control group.
There were significant differences in child Pugh score, average he grade, average he attack, blood ammonia level and serum zinc level between the two groups 6 months after treatment (P = 0.04, P = 0.03, P = 0.02, P = 0.01, P < 0.001). The prevalence of zinc deficiency decreased significantly after 6 months (P < 0.001), but no significant change was observed in the control group (P = 0.10). At the end of the study period, he improved in 21 subjects (responders) in the zinc group and 10 subjects in the control group (54% vs 26%, P = 0.03). At the end of the study, 16 subjects in the zinc group achieved grade 0 he, while only 6 subjects in the control group improved to grade 0 he (41% vs 16%, P = 0.02).
Zinc can improve the average value of each NP test (nct-a, P < 0.0001; nct-b, P < 0.001; DST, P < 0.01), and the difference between the two groups at 6 months after treatment is also improved, with statistical significance (nct-a, P < 0.01; nct-b, P < 0.01; DST, P = 0.02) (Table 3).
After taking zinc for 6 months, the frequency of abnormal results in each NP test decreased significantly (nct-a, P < 0.001; nct-b, P < 0.01; DST, P = 0.02). However, no significant changes were observed in the control group (nct-a, P = 0.71; nct-b, P = 0.06; DST, P = 0.44). A significant change in the mean number of abnormal NP tests was observed between the two groups (P = 0.04).
Table 3 changes of clinical and laboratory parameters at 6-month follow-up
2.5 relationship between HRQoL and clinical variables
Univariate correlation between clinical variables and 6-month changes of SF-36 total scores (△ PCs and △ MCS) was analyzed. In univariate analysis, zinc supplementation and blood ammonia levels were significantly correlated with △ PCs (P = 0.02, P = 0.04), but not with △ MCS. In multivariate analysis, zinc supplementation was the only factor affecting △ PCs (P = 0.03), but had no significant effect on △ MCS (Table 4).
Table 4 predictors of PCs and MCS changes (n = 77)
On the basis of standard treatment, the addition of ppz can significantly improve liver function, hepatic encephalopathy (he), neuropsychological (NP) test and health-related quality of life (HRQOL), especially physical health (PCs, P = 0.04), but not mental health (MCS) (P = 0.95). Compared with standard treatment, zinc supplementation significantly reduced the grade of hepatic encephalopathy and blood ammonia level (P = 0.03, P = 0.01), and improved child Pugh score and NP test (P = 0.04, P = 0.02). In multivariate analysis, zinc supplementation was significantly correlated with the improvement of PCs (P = 0.03), but not with the change of MCS (P = 0.98). In a word, in terms of improving the health-related quality of life of patients, reyleson (polyprazeb granules) may be an effective drug for the treatment of he, which can significantly reduce the classification of hepatic encephalopathy and blood ammonia level, improve the quality of life of patients, and provide new treatment options for he patients.
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