Applied nutritional investigationEffect of zinc on liver cirrhosis with hyperammonemia: A preliminary randomized, placebo-controlled double-blind trial
Introduction
Protein-energy malnutrition in patients with liver cirrhosis can degrade their prognoses for survival and cause complications such as hepatic encephalopathy [1], [2], [3], [4], [5], [6]. The effectiveness of several nutritional interventions on nutritional and metabolic abnormalities associated with liver cirrhosis has been described. The administration of branched-chain amino acids improves protein metabolism, reducing the incidence of complications and improving prognosis for survival [7], [8], [9]. Additionally, consuming foods divided more than three times per day can improve abnormal energy metabolism [10]. Thus, the management of nutritional factors is clinically important when treating liver cirrhosis. Recently, among various nutrients, trace metals such as iron and zinc were found to be closely involved in the pathophysiology of liver cirrhosis [11], [12], [13], [14]. To date, however, the mechanisms underlying their metabolism and pathologic significance have not been clarified.
Zinc plays an indispensable role in cell growth and differentiation and is very important for metabolism in humans [15]. More than 300 proteins contain domains with zinc, and these domains are important for regulating cellular functions [16], [17], [18], [19]. Therefore, it is likely that zinc is closely involved in many bodily functions. The homeostasis of zinc in vivo is primarily preserved by a balance between the zinc-binding protein metallothionein and the expression of two zinc transporters [20], [21], [22], [23], [24]. If zinc stores become deficient, numerous problems, including growth disorder, cognitive disorder, and compromised immune function, can occur [25], [26], [27], [28]. Zinc deficiency is likely to occur in patients with liver cirrhosis, and factors that are potentially responsible for such deficiency include disturbed zinc absorption by the digestive tract and increased zinc excretion in the urine [12], [13]. Furthermore, diuretics, which are commonly used to treat edema and ascites, aggravate zinc deficiencies in patients with liver cirrhosis by increasing zinc excretion in the urine [29].
It has been suggested that zinc deficiency is related to the pathogenesis of hepatic encephalopathy. Several studies have shown a statistically significant inverse relationship between the serum levels of zinc and ammonia [30], [31], [32]. On the basis of these findings, several studies have examined the effects of zinc supplementation in patients with hyperammonemia [30], [33], [34], [35], [36]. Although two randomized controlled trials (RCTs) have been performed to examine these effects, the period of zinc supplementation in these trials was rather short (8 and 10 d), and the results were controversial [33], [37]. One study showed that longer supplementation (3 mo) of zinc in patients with hepatic encephalopathy reduced serum ammonia levels and increased plasma urea levels, but this was not an RCT [14]. The main effects of zinc supplementation on ammonia metabolism proposed thus far are increased ammonia uptake of the muscle through activation of glutamine synthetase and increased activity of ornithine transcarbamylase, a key enzyme of the urea cycle in the liver [13]. Liver ornithine transcarbamylase activity was found to decrease in zinc-deficient rats, leading to increased plasma ammonia, whereas it significantly increased in zinc-supplemented cirrhotic rats compared with the control group [34].
In this study, we describe the results of a multicenter, placebo-controlled, double-blind randomized trial of zinc administration for 3 mo in patients with liver cirrhosis and hyperammonemia.
Section snippets
Participants
Between September 2009 and January 2012, patients who met the following criteria were enrolled at each institution: liver cirrhosis diagnosed by clinical symptoms, imaging studies, or histologic examination; blood ammonia level higher than the institutional reference value confirmed at least twice from blood samples collected within 2 mo before enrollment; hepatic encephalopathy grade ≤1 (grade 0, no symptoms; grade 1, the presence of euphoria or depression, mild confusion, slowness, or
Analysis set
Eighteen patients who met the inclusion criteria at each institution were enrolled and assigned to either the P group (n = 8) or the Z group (n = 10) (Fig. 1). One patients in the P group dropped out of the study due to general fatigue and another due to development of liver cancer requiring treatment. These two patients were thus excluded from the analysis. Because the patient who developed liver cancer had received treatment for hepatocellular carcinoma before this trial, the liver cancer was
Discussion
It has long been known that patients with chronic liver disease, especially liver cirrhosis, are deficient in zinc, a status that may contribute to several clinical symptoms of liver cirrhosis, and could be relieved by zinc replacement [12], [13], [14], [33], [34], [35], [36]. However, although the effects of short-term (about 10 d) zinc supplementation have been studied via a double-blind randomized controlled method, the effects of long-term administration (>1 mo) have not yet been examined,
Conclusion
Although our results are only preliminary, this trial showed the effects of zinc supplementation for 3 mo on improving ammonia metabolism in patients with liver cirrhosis, and it presents promising data indicating the importance of RCTs with larger sample sizes and longer treatment durations for further elucidating the clinical efficacy of zinc preparations.
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This work was supported by a Grant-in-Aid for research on refractory hepatitis from Ministry of Health, Labour and Welfare, Japan (H20-heptitis-general-005). KK, SN, HK, KS, IS, YU, DH, HM, and KS were responsible for the conception and design of the study. KK, MS, TK, RE, KS, AK, and TI were responsible for generation, collection, assembly, and/or interpretation. KK drafted the manuscript. HM and KS revised the manuscript. All authors read and approved the final version of the manuscript. The authors have no conflicts of interest to declare.