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- Materials and methods
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 studies5, 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.9–11 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.
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- Materials and methods
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 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.
Katayama29 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 improve NP tests.30, 31
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 study32 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 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 patients with decompensated liver cirrhosis.24, 33, 34 In particular, HE and Child-Pugh score negatively correlated with physical health more than mental health in the SF-36.24, 34–36 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, 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 200–600 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-peptic-ulcer drug.39l-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 studies43, 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.