Polaprezinc is composed of zinc and L-carnocin. In Japan, it has been used to treat gastric ulcers in general clinical practice since 1994. The medicine we used in this study was Promac granules, 1.0 g/day. Promac contains 150 mg of polaprezinc per gram and also contains D-mannitol, cornstarch, calmerose calcium, polyvinyl pyrrolidone K, and aminoalkylacrylate polymer E as additives. Promac was administered orally twice a day, after breakfast and after dinner, to a total of 1.0 g. Therefore, the daily administration of zinc was 33.9 mg. In this study, we compared the long-term outcome between the Promac (polaprezinc) administration group and the untreated group. The results showed that, in the polaprezinc administration group, the average serum zinc concentrations had increased by 9.8% three years after the treatment started compared to the level before the start of treatment. However, in the untreated group, the serum zinc concentrations had decreased by approximately 5% compared to the level at the commencement of therapy. There were fifteen cases (46.9%) in the polaprezinc administration group whose serum zinc concentrations increased, significantly more than in the untreated group, in which there was only one case (3.3%). On the contrary, the patients whose serum zinc concentrations decreased numbered only five (15.6%) in the polaprezinc administration group but 15 (50%) in the untreated group. Therefore, it was confirmed that the serum zinc concentrations increased following the administration of polaprezinc, even in patients with C-viral CH or LC.
In this study, polaprezinc was administered at a fixed amount, regardless of the height and/or weight of the patient. When the changes in serum zinc concentrations were compared according to the daily dose of zinc administered per kg body weight, the number of patients who became zinc responders was significantly higher in the group of patients of lower weight (data not shown). Therefore, it suggested that there were cases in which administration of the daily dose of 150 mg polaprezinc was insufficient. In fact, in the group that was administered a daily dose of zinc below 0.6 mg/kg, the serum zinc concentrations increased slightly immediately after the start of administration, but after that a tendency to decrease was observed. However, in the group that was administered a daily dose of zinc above 0.6 mg/kg, the serum zinc concentrations increased gradually after the start of administration and exceeded the levels in the group administered a daily dose of zinc less than 0.6 mg/kg. Therefore, when polaprezinc is used clinically, attention must be paid to the individual’s body weight.
Comparing the long-term outcomes, the polaprezinc administration group showed a clear reduction in ALT and AST levels, compared to the untreated group. Although the platelet counts decreased compared to the level at the start of administration, the reduction was clearly less than that of the untreated group. The ALT and AST levels also had a tendency to decrease in the group with increased zinc concentrations. Therefore, this prospective study confirmed that the serum zinc concentrations gradually reduced without zinc supplementation in patients with C-viral CH or LC. The serum zinc concentrations increased or remained unchanged in 84.3% of patients with C-viral chronic liver disease when zinc was administered, but 15.6% of patients showed a reduction in their zinc concentrations. It is known that serum zinc concentrations decreased in patients with liver disease in parallel with the development of disease stage because zinc absorption from the intestine decreases and the zinc content of the liver reduces due to the decrease in the number of functional hepatocytes [18
]. However, our study suggests that the serum zinc concentrations can increase in the majority of patients if a sufficient quantity of zinc is administered.
When the patients administered polaprezinc were divided into two groups whose serum zinc concentrations were more than 64 µg/dl (high zinc group) and less than 64 µg/dl (low zinc group), the reduction of AST and ALT levels in the low zinc group was significantly greater than in the high zinc group. Therefore, zinc supplementation in patients with CH or LC with low serum zinc concentrations was more effective than in those with high serum zinc concentrations. Specifically, patients with low serum zinc concentrations seemed to achieve a greater reduction in serum AST or ALT levels following zinc supplementation, regardless whether the zinc concentration increased or decreased. On the other hand, patients with high serum zinc concentrations, whose serum zinc concentrations did not increase with the daily dose of zinc given, also did not achieve a reduction of ALT levels and perhaps require a greater degree of zinc supplementation. The significance of maintaining the serum zinc concentrations at a high level in C-viral liver disease is that, by achieving a continuous low level of ALT, it is possible to slow the progression of liver fibrosis and, further, to restrain the development of liver carcinogenesis. Also, in patients with a decreased reserve of liver function, such as those with decompensated cirrhosis, it is possible to prolong the survival period by increasing their zinc concentrations, leading to improvement in hyper-ammonia and recovery of liver function. Our study showed no significant difference in the cumulative incidence of HCC between the group administered polaprezinc and the untreated group. However, comparing the zinc responders and zinc non-responders, regardless of polaprezinc administration, the cumulative incidence of HCC was significantly lower in the former, suggesting that the influence of zinc supplementation on the long-term outcome of C-viral CH or LC is significant. Therefore, we report that zinc supplementation for C-viral CH or LC is clinically useful.
Multivariate analysis of the clinical background factors was performed on the zinc non-responders in the group administered polaprezinc. The results showed that there was no significant relationship between the age, body weight or BMI, platelet count, ALT level, AST level, or the HCV RNA level. However, when the changes in the serum zinc concentrations were evaluated according to the daily dose of zinc administered per kg body weight, in the polaprezinc administration group for whom the daily dose of zinc was more than 0.6 mg/kg the number of cases whose serum zinc concentrations increased compared to the level before the start of therapy was significantly high, whereas in the group with zinc administration at daily dose of zinc less than 0.6 mg/kg the number of cases whose serum zinc concentrations decreased was significantly high. Therefore, it seems necessary to consider the daily dose of zinc administered per kg body weight on an individual basis and to increase the daily dose of zinc administered per day for patients of greater body weight. In addition, the data suggest that, for the zinc non-responders in the polaprezinc administration group, increasing the daily dose of polaprezinc could lead to an improvement in the long-term outcome of the patient.
As for the reason why ALT and AST levels reduced with zinc administration, the following may be suggested: It is known that zinc has an anti-oxidant effect. It has an inhibitory action on iron-dependent radical reactions and on lipid peroxidation. It has been assumed that the state of zinc deficiency in chronic liver disease first leads to an increase in hepatic phospholipids, resulting in intensification of lipid peroxidation, and thereby causes hepatic cell injury [23
]. Therefore, it is assumed that zinc administration inhibits lipid peroxidation and subsequently alleviates hepatic cell injury and improves the AST and ALT levels. Zinc complexes with ferritin in hepatocytes. With zinc administration, complexing of zinc and ferritin also increases in the liver. This zinc-ferritin complex is readily used by apoenzymes that require zinc. Therefore, it is suggested that the ferritin level in hepatocytes may decrease with increasing zinc concentration, and zinc consequently enhances the chelation of iron in the liver. As a result, there should be a reduction in oxidative stress from iron in the hepatocytes and a decrease in aminotransferase levels [25
]. In fact, it has been reported that the action of polaprezinc inhibiting gastric mucosal injury is due to the strong anti-oxidant action and membrane stabilizing action [26
]. Therefore, in a similar manner in the liver, liver function improves and liver fibrosis is suppressed by the anti-oxidant action and membrane stabilization effect of polaprezinc. The reason the incidence of HCC in zinc responders may be reduced more than that of zinc non-responders may be as follows: Serum ALT or AST levels reduced through the anti-oxidant effect of zinc. Also, zinc deficiency is known to affect certain mediators of innate immunity, such as the function of neutrophils, NK cells and complement [29
]. Furthermore, the numbers and activity of NK cells are dependent on serum zinc concentrations [31
]. Zinc supplementation results in significantly greater numbers of cytotoxic and helper T and NK cells than are seen in the control group [32
Finally, we also compared the changes of serum zinc concentrations, levels of AST and ALT, and the cumulative incidence of HCC development between the patients with CH and those with LC. The serum zinc concentrations increased and the serum levels of AST and ALT were reduced after three years of polaprezinc administration in both groups. Furthermore, in the CH group, the cumulative incidence of HCC development in the zinc responders was significantly lower than that in the zinc non-responders. However, the cumulative incidence of HCC development did not differ significantly between the zinc responders and non-responders in the LC group. We assume that liver cirrhosis constitutes a high carcinogenic state and the development of HCC could not be prevented simply by polaprezinc administration.
In conclusion, we performed zinc supplementation for patients with C-viral CH and LC and the following results were obtained: The serum zinc concentration increased in approximately half of the patients who received the zinc supplement. Compared to the untreated patients, the AST and ALT levels decreased significantly. Compared to the untreated patients, the reduction in the platelet counts was significantly lower. The factors that inhibited increases in serum zinc concentrations following administration of polaprezinc included low serum zinc concentration states such as liver cirrhosis. Furthermore, the reductions of AST and ALT levels in the low zinc group were significantly greater than those of the high zinc group. The zinc responders had a significantly lower cumulative incidence of HCC than the zinc non-responders.Thus, it was confirmed that zinc supplementation for patients with C-viral CH or LC improves both the degree of the liver damage and the long-term outcome.