Open Journal of Gastroenterology, 2011, 1, 28-34
doi:10.4236/ojgas.2011.12005 Published Online November 2011 (
Published Online November 2011 in SciRes.
Effect of zinc supplementation in patients with type
C liver cirrhosis
Kazuhiro Katayama1, Mitsuru Sakakibara1, Kazuho Imanaka1, Kazuyoshi Ohkawa1,
Takashi Matsunaga1, Masafumi Naito2, Toshifumi Ito2
1Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka,
2Department of Internal Medicine, Osaka Koseinenkin Hospital, Osaka, Japan.
Received 16 September 2011; revised 25 October 2011; accepted 4 November 2011.
Zinc is often deficient in patients with liver cirrho-
sis, and treatment with zinc provides short-term
improvement in protein metabolism. However, the
long-term effects of zinc have not been fully clari-
fied. The present study aimed to analyze the effect
of zinc on the long-term clinical course, especially
hepatocarcinogenesis, in type C liver cirrhosis. Am-
ong patients with type C liver cirrhosis visiting our
hospital between June 1998 and January 2009, th-
ose with a serum albumin level 3.5 g/dL and a
serum zinc level 70 μg (1.07 μmol)/dL were se-
lected. Thirty-seven patients were randomly di-
vided into 2 groups: group B (12 g/day branched-
chain amino acid granules) and group BZ (same as
group B plus 100 mg/day - 600 mg/day zinc sulfate
or 150 mg/day - 225 mg/day polaprezinc). Multi-
variate analysis revealed that the administration of
zinc was not a significant determinant, but pre-
treatment serum zinc levels (hazard ratio [HR],
0.921; 95% confidence interval [CI], 0.853 - 0.994)
and serum zinc levels less than 80 μg (1.22 μmol)/dL
12 months after beginning this study (HR, 6.866;
95% CI, 1.399 - 33.707) were significant determi-
nants of carcinogenesis and death. Serum albumin
levels in patients whose serum zinc levels had not
increased up to 80 μg/dL by the third year of this
study were significantly lower (p = 0.023) than
those of patients that had increased up to 80 μg/dL.
Conclusio ns: In type C liver cirrhosis with zinc de-
ficiency, administration of zinc does not improve
cancer-free survival. However, serum zinc levels
can predict outcomes in patients with type C liver
cirrhosis. However, although zinc may play a role in
hepatocarcinogenesis, the precise implications re-
main to be clarified.
Keywords: Hepato-Carcinogenesis; Trace Element;
Protein Metabolism
Primary liver cancer is one of the leading causes of death
from cancer [1,2]. Hepatitis B and C viruses play an
important role in the pathology of hepatocellular carci-
noma [2-4]. Although antiviral treatment regimens such
as combined Peg-interferon plus ribavirin therapy for
hepatitis C and nucleic acid analogue therapy for hepati-
ctis B have lowered the incidence of liver cancer, these
regimens do not completely prevent carcinogenesis [2,5,
6]. Factors other than hepatitis viruses also play impor-
tant roles in the pathogenesis of hepatocellular carci-
noma. Conditions involving metabolic abnormalities su-
ch as nonalcoholic fatty liver disease, obesity, and dia-
betes mellitus have been suggested to be risk factors for
liver carcinogenesis [2,7-10]. Liver cirrhosis patients
have been shown to have abnormal amino acid balance
due to branched chain amino acid (BCAA) deficiency,
and replacement of BCAAs has been shown to improve
event-free survival and liver function in patients with
liver cirrhosis [9,10]. These findings suggest that ab-
normal amino acid metabolism may aggravate liver cir-
rhosis. In addition, administration of BCAAs has been
shown to significantly suppress liver carcinogenesis in
obese individuals with a body mass index of at least 25
[9,10]. Therefore, metabolic abnormalities associated
with liver disease are involved in various pathological
conditions; however, their mechanisms have not been
fully clarified.
Zinc, which is a trace metal, is indispensable for
growth and differentiation of cells, and is one of the
most important nutrients of metabolism in humans [11].
More than 300 proteins possess a zinc-containing region,
K. Katayama et al. / Open Journal of Gastroenterology 1 (2011) 28-34 29
and these proteins play an important role in the regula-
tion of cell function [12-15]. Therefore, Zinc may be
closely involved in many bodily functions. Homeostasis
of zinc in vivo is primarily maintained by a balance be-
tween zinc-binding metallothionein protein and the ex-
pression of 2 key zinc transporters [16-20]. Deficiency
of zinc can lead to growth disorders, cognitive disorders,
and compromised immune function [21-24]. Further-
more, zinc deficiency can accompany liver cirrhosis,
leading to abnormal levels of ammonia and other sub-
stances due to abnormal protein metabolism, and the
onset of hepatic encephalopathy [25,26]. Zinc replace-
ment has been shown to alleviate hepatic encephalopa-
thy and hyperammonemia and to improve protein me-
tabolism [25,26]. We previously showed that combined
BCAA plus zinc treatment is more effective in alleviat-
ing abnormal ammonia metabolism and abnormal amino
acid balance than BCAA monotherapy [27]. However,
there are very few reports on the long-term efficacy of
zinc replacement therapy [28,29]. In this study, we ana-
lyzed the effect of zinc supplementation and the rela-
tionship between serum zinc levels and the long-term
course, especially hepatocarcinogenesis, of hepatitis C
virus-related liver cirrhosis.
2.1. Subjects
Among the patients with hepatitis C virus-related liver
cirrhosis visiting our facility between June 1998 and
January 2009, those satisfying all the following criteria
were enrolled in the study: (1) serum albumin levels no
higher than 3.5 g/dL; (2) serum zinc levels no higher
than 70 μg (1.07 μmol)/dL; (3) patients were able to
receive periodical outpatient care, and (4) patients pro-
vided informed consent to the study. Patients who were
already treated with BCAA granules, those with a posi-
tive history of liver cancer, those having esophageal or
gastric varix, which needed to be treated, and patients
scheduled to receive antiviral therapy (e.g., interferon)
during the study period were excluded from the study.
Other exclusion criteria included coinfection with hepa-
titis B virus or human immunodeficiency virus. Patients
who developed liver cancer within 6 months after the
start of the study were also excluded.
2.2. Protcol
These 37 subjects were randomized into 2 groups: group
B (n = 16, treatment with 12 g/day BCAA granules; Li-
vact, Ajinomoto Pharmaceutical Co., Ltd., Tokyo, Japan)
and group BZ (n = 21, treatment with 12 g/day BCAA
granules plus zinc preparation). In group BZ, the zinc
preparation initially used was 600 mg/day zinc sulfate
(containing 136 mg zinc, 2.08 mmol zinc) for patients
with a serum zinc level no higher than 50 μg (0.76
μmol)/dL and either 200 mg/day zinc sulfate (containing
45 mg zinc, 0.69 mmol zinc) or 150 mg/day polaprezinc
(containing 34 mg zinc, 0.52 mmol zinc; Zeria Pharma-
ceutical Co., Ltd., Tokyo, Japan) for patients with serum
zinc levels between 50 and 70 μg (0.76 μmol and 1.07
μmol)/dL. If serum zinc levels did not reach 80 μg (1.22
μmol)/dL, the zinc sulfate dose was later increased up to
600 mg (2.08 mmol)/day. If serum zinc levels exceeded
120 μg (1.83 μmol)/dL, the zinc sulfate dose levels were
reduced. Zinc dose levels were also reduced in patients
with complaints of nausea or anorexia after the start of
zinc treatment. The background variables of the patients
are summarized in Table 1. There were no serious ad-
verse events during the study. There were no significant
differences in any background variables between the 2
groups (Table 1). In this open-label clinical study, the
subjects were randomly allocated to groups B and BZ at
a ratio of 1:1 in the following manner. All patients visit-
ing our hospital were assigned serial case numbers for
the purpose of identification. Among the patients who
had provided informed consent to the study, those who
had even case numbers were allocated to group BZ and
those who had odd case numbers were allocated to group
B. The patients were followed up at intervals of 2 - 3
months by means of a hematological test and abdominal
ultrasonography or computed tomography/magnetic re-
sonance imaging. The primary endpoint of this study
was cancer free survival. The follow-up was completed
upon diagnosis of liver cancer or death. The follow-up
period (mean ± SD) was 1152 ± 698 days. During the
study period, prophylactic endoscopic treatment of varix
Table 1. Patient data.
Group B (n = 16) Group BZ (n = 21)P
Age (years) 64.9 ± 10.3 68.7 ± 6.5 0.4807
Sex (male/female) 8/8 11/10 0.8859
Body Mass Index 23.5 ± 3.0 24.0 ± 3.5 0.7359
T.Bil (mg/dL) 0.98 ± 0.35 1.20 ± 0.55 0.2503
Albumin (g/dL) 3.4 ± 0.2 3.3 ± 0.2 0.3498
Zinc (g/dL) 59.5 ± 9.8 58.0 ± 8.6 0.4619
Fischer ratio 1.92 ± 0.54 1.58 ± 0.48 0.0806
Ammonia (g/dL) 36.4 ± 14.4 49.6 ± 29.4 0.2088
PT (%) 78.6 ± 14.2 72.1 ± 13.9 0.1042
ALT (IU/L) 61.6 ± 37.5 61.5 ± 29.0 0.8301
WBC (/L) 4019 ± 1212 3881 ± 922 0.8181
Hb (g/dL) 12.5 ± 1.7 12.6 ± 1.4 0.7709
Platelets (×104/L) 12.0 ± 6.8 9.5 ± 3.2 0.5500
FBS (mg/dL) 107.4 ± 17.1 97.1 ± 10.4 0.0554
AFP (ng/ml) 35.8 ± 40.9 48.0 ± 82.4 0.9755
Values are expressed as mean ± s.d. PT, prothrombin time. ALT, alanine
transaminase. FBS, fasting blood sugar. AFP, alfa-feto protein. P value
between two groups was calculated by Man-Whitney U test, except sex. P
value of sex was calculated by chi-square test.
opyright © 2011 SciRes. OJGas
K. Katayama et al. / Open Journal of Gastroenterology 1 (2011) 28-34
and treatment of ascites or edema with diuretics, were
administered as needed. In addition, rupture of esophag-
eal/gastric varix did not occur in any patient, because
risky varices were prophylactically treated. Inter-group
comparison was performed to determine the time de-
pendent changes in parameters such as age, sex, body
mass index, total bilirubin, serum albumin levels, proth-
rombin time (PT), aspartate transaminase (AST) levels,
alanine transaminase (ALT) levels, ammonia levels,
platelet count, Fischer ratio (FR), pretreatment serum
zinc levels, and fasting serum glucose levels during the
first 3 years of treatment. We also compared use/non-
use of zinc preparation (BZ vs. B) and response/no re-
sponse to serum zinc levels (serum zinc levels of 80 μg
(1.22 μmol)/dL or higher 12 months after the start of
treatment/serum zinc levels less than 80 μg/dL 12
months after the start of treatment). This clinical study
was approved by the institutional review board, and all
patients provided consent to the study either orally or in
2.3. Statiscal Analysis
Statistical analysis was performed using the computer
program Dr. SPSS II for Windows (SPSS Co., Ltd., To-
kyo, Japan). We used the Mann-Whitney U test or chi-
square test for inter-group comparisons of background
variables. The cumulative cancer-free survival rate of
each group was determined by the Kaplan-Meier method.
The significance of differences was analyzed by log rank
test. The Cox proportional hazards model was used for
evaluating the hazard ratio with regard to carcinogenesis
and death.
3.1. Comparison of Serum Zinc Levels between
the Groups
Serum zinc levels were significantly increased at 1 years
- 3 years after treatment in group BZ compared with
those in group B (Figure 1).
3.2. Factors Associated with Cancer-Free Survival
First, we performed univariate analysis of factors asso
ciated with carcinogenesis and death by using a Cox
hazards model. The results of this analysis are shown in
Table 2. Among the factors analyzed, 5 factors (response
to serum zinc levels, FR, PT, platelet count, and pre-
treatment serum zinc levels) had a p value 0.10. Mul-
tivariate analysis using these 5 factors indicated that the
response to serum zinc levels and pre-treatment serum
zinc levels were significant factors, with the former be-
ing the most potent factor (Table 3). Therefore, we
compared the cumulative cancer-free survival rate be-
tween group H ( patients with elevated serum zinc levels
more than 80 μg/dl after the administration of zinc prepa-
Figure 1. Time course of serum zinc levels during 3 years of
treatment (box plot; median, 10th - 90th percentile and 25th -
75th percentile; circles show outliers). Comparison between
group B (gray boxes) and group BZ (white boxes). Zinc levels
were significantly higher in Group BZ than those in Group B
throughout the 3-year period.
Table 2. Factors associated with hepatocarcinogenesis and
death by univariate analysis.
Factor HR 95%CI p
Age (years) 0.984 0.929 - 1.0420.587
Sex (male/female) 0.797 0.258 - 2.4580.692
Body Mass Index 1.066 0.905 - 1.2550.446
T.Bil (mg/dL) 2.200 0.643 - 7.5210.209
Albumin (g/dL) 0.273 0.025 - 3.0100.289
PT (%) 0.936 0.882 - 0.9330.028
AST (IU/L) 0.985 0.946 - 1.0060.150
ALT (IU/L) 0.990 0.972 - 1.0080.266
FBS (mg/dL) 0.987 0.951 - 1.0850.500
Platelets (×104/L) 0.796 0.649 - 0.9760.029
Fischer ratio 0.261 0.1 - 1.124 0.071
Pre-treatment Zinc (g/dL) 0.932 0.871 - 0.9960.037
Zinc at 12-month < 80 (g/dL) 4.161 0.928 - 18.6500.062
BZ (vs B) 0.957 0.320 - 2.8640.937
HR, hazard ratio. CI, confidence interval. PT, prothrombin time. FR, Fisch-
er ratio. AST, aspartate transaminase. ALT, alanine transaminase.
Table 3. Factors associated with hepatocarcinogenesis and
death by multivariate analysis.
Factor HR 95%CI p
Zinc at 12-month < 80 (g/dL) 6.866 1.99 - 33.7070.010
Pre-treatment Zinc (g/dL) 0.921 0.853 - 0.9940.043
PT (%) 0.946 0.94 - 1.002 0.058
rations) and group L (other patients including patients
who did not receive zinc supplementation) (Figure 2).
The incidence of cancer and the death rate were signifi-
cantly lower in group H than those in group L (p = 0.0432,
log rank test). We compared the background variables
between groups H and L (Table 4). Fasting blood sugar
(FBS) of group H was significantly lower than in group L.
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K. Katayama et al. / Open Journal of Gastroenterology 1 (2011) 28-34 31
3.3. Time Course of Changes in Hematological
Serum albumin levels tended to be higher in group H
than in group L during the second year and were signifi-
cantly higher during the third year (p = 0.023, Figure
3(a)). No significant differences were observed in PT
and ALT levels between the 2 groups (data not shown).
We estimated the percentage change in serum ammonia
levels from the pretreatment baseline levels and found
that serum ammonia levels tended to decrease after the
start of treatment in group H and were significantly low-
er in the third year compared with those in group L
(Figure 3(b)). Platelet count was not significantly dif-
ferent between the 2 groups (data not shown). The FR
was significantly higher in group H than that in group L
during the third year (p = 0.035, Figure 3(c)).
Factors known to be involved in carcinogenesis from
chronic liver disease include hepatitis viruses, alcohol
consumption, and smoking [2,30]. In addition, several
metabolic factors have recently been shown to be asso-
ciated with liver carcinogenesis. Obesity and diabetes
mellitus are risk factors for liver carcinogenesis [2], and
it has been suggested that iron is involved in carcino-
genesis in patients with hepatitis C virus-related chronic
liver disease [31]. In patients with chronic viral liver
disease, antiviral therapy (e.g., interferon therapy for
chronic hepatitis C and nucleic acid analog therapy for
hepatitis B virus-related chronic liver disease) has been
shown to suppress carcinogenesis; however, antiviral
therapy alone cannot completely prevent liver carcino
genesis in these patients [2,5,6]. Furthermore, as was the
case in this study, in hepatitis C virus-related chronic
05001000 15002000 2500 3000 3500
Logrank p=0.0432
Cancer-free survival rate
Figure 2. Comparison of cumulative cancer-free survival rate
between group H (solid line) and group L (dotted line) (Kap-
lan-Meier method). The cancer-free survival rate was signifi-
cantly higher in group H than that in group L (log rank test).
Table 4. Patient data.
Group H (n = 13) Group L (n = 24)p
Age (years) 57.5 ± 9.9 68.8 ± 8.9 0.8362
Sex (male/female) 7/6 12/12 0.8231
Body Mass Index 23.2 ± 3.7 24.1 ± 3.0 0.5241
T.Bil (mg/dL) 1.09 ± 0.65 1.12 ± 0.38 0.4940
Albumin (g/dL) 3.4 ± 0.2 3.4 ± 0.2 0.4172
Zinc (g/dL) 57.3 ± 8.9 59.6 ± 9.2 0.3646
Fischer ratio 1.68 ± 0.54 1.76 ± 0.53 0.8114
Ammonia (g/dL) 54.8 ± 35.5 36.0 ± 14.0 0.1522
PT (%) 76.2 ± 16.1 74.3 ± 13.4 0.5886
ALT (IU/L) 58.8 ± 24.2 64.0 ± 36.6 0.9746
WBC (/L) 4008 ± 911 3904 ± 1126 0.7026
Hb (g/dL) 12.7 ± 1.3 12.5 ± 1.6 0.6332
Platelets (×104/L) 10.7 ± 3.3 10.5 ± 6.0 0.2391
FBS (mg/dL) 94.8 ± 10.4 105.2 ± 15.2 0.0386
AFP (ng/ml) 26.2 ± 29.2 51.7 ± 79.8 0.3992
Values are expressed as mean ± s.d. PT, prothrombin time. ALT, alanine
transaminase. FBS, fasting blood sugar. AFP, alfa-feto protein. P value
between two groups was calculated by Man-Whitney U test, except sex. P
value of sex was calculated by chi-square test.
(a) (b)
Figure 3. Time course of serum levels during 3 years of treat-
ment (box plot; median, 10th - 90th percentile and 25th - 75th
percentile, circles show outliers). (a): Comparison of serum
albumin levels between group B (gray boxes) and group H
(white boxes). Albumin levels were significantly higher in
group H than those in group L in the third year. Statistical
analysis was performed by Mann-Whitney U test; (b): The
percent change in serum ammonia levels from pretreatment
levels in group L (gray boxes) and group H (white boxes).
Group H showed a significantly greater percent reduction than
group L. Statistical analysis was performed by Mann-Whitney
U test; (c): Comparison of FR between group L (gray boxes)
and group H (white boxes). The FR was significantly higher in
group H than that in group L in the third year. Statistical analy-
sis was performed by Mann-Whitney U test. FR, Fischer ratio.
opyright © 2011 SciRes. OJGas
K. Katayama et al. / Open Journal of Gastroenterology 1 (2011) 28-34
liver disease with advanced liver fibrosis, interferon
therapy is often difficult because of complications such
as thrombopenia [32,33]. Therefore, in addition to anti-
viral therapy, it is important to investigate metabolic
factors that possibly suppress carcinogenesis.
It has been shown that zinc, which is a trace metal, is
deficient in patients with chronic liver disease and is
involved in metabolic abnormalities primarily pertaining
to ammonia; these metabolic abnormalities can be alle-
viated by zinc replacement [25,26]. However, to date,
the relationship between long-term effects of patients
with liver disease and the metabolic function of zinc has
not been sufficiently studied.
In the present study, administration of zinc prepara-
tions did not significantly affect cancer-free survival.
However, in patients with elevated serum zinc levels
(80 μg/dL, 1.22 μmol/dL) after the administration of
zinc preparations, the rate of hepatocarcinogenesis and
death was significantly reduced, suggesting that the se-
rum zinc level might be an important predictor of can-
cer-free survival. Although the present study was pre-
liminary, it showed for the first time that serum zinc lev-
els are a crucial predictor of clinical outcomes. Matsu-
oka et al. also studied the effect of long-term zinc sup-
plementation, and showed that there were improved
clinical outcomes in patients whose serum zinc levels
were increased [29]. However, the dose of zinc adminis-
tered to patients in their study was small compared with
that in the present study (34 mg vs. 136 mg zinc, 0.52
mmol vs. 2.08 mmol), and they did not show a relation-
ship between the serum level of zinc and clinical out-
The exact mechanism of zinc for the improvement of
cancer-free survival is still debatable. One possible ex-
planation is that the effect of zinc might be due to im-
proved nitrogen metabolism such as serum albumin lev-
els and FR in group H. Zinc is known to be involved in
metabolism of ammonia as a coenzyme of ornithine
transcarbamylase (one of the enzymes of the hepatic
urea cycle) [26,34]. In patients with chronic liver disease,
the ability of detoxicating ammonia is reduced because
of zinc deficiency, and this can be improved by zinc re-
placement [25,26]. Because ammonia is also metabo-
lized in skeletal muscles by consuming BCAAs, im-
provement in ammonia detoxification in the liver is ex-
pected to reduce BCAA consumption. This can lead to
alleviation of BCAA deficiency and improvement in
amino acid imbalance [27,34]. Indeed, we previously
showed that zinc treatment contributes to improving
amino acid imbalance [27]. Administration of BCAAs as
a drug improves the prognosis of patients with chronic
liver disease [9,10], and survival is better in patients
with a high serum FR [34]. Therefore, it is possible that
the effects of zinc are due to an improvement in nitrogen
metabolism. The fact that patients with liver cirrhosis
may suffer from malnutrition and other deficiencies
means that other possible reasons for the reduction in
cancer-free survival should be considered. We compared
other nutritional factors between group H (patients with
serum zinc levels > 80 μg/dl (1.22 μmol/dl at 12-month
of this study) and group L (other patients) (Table 4).
There were no significant differences between the
groups in terms of body mass index or hemoglobin, but
FBS was significantly lower in group H than in group L.
However, FBS was not significantly associated with
cancer-free survival in univariate analysis (Table 2).
Thus, although this study could not rule out the possibil-
ity that factors other than zinc might affect patients out-
comes, serum zinc levels nonetheless appear to play
some an important role in predicting cancer-free survival.
The magnitude of elevation in serum zinc levels after
administration of zinc preparations differs among indi-
viduals. A transporter is involved in zinc absorption in
the small bowel mucosa, and the expression of this
transporter has been suggested to be affected by zinc
exhaustion [17-20]. It is difficult to observe this effect
during clinical practice, and it is unknown how to adjust
serum zinc levels based on this effect. In the current
study, the administered zinc level 12 months after the
start of treatment was not significantly different between
group H and group L. The reason why there was no ele-
vation in serum zinc levels in some cases but sufficient
elevation in others remains unknown and should be in-
vestigated in the future. However, an analysis of indi-
vidual cases revealed an increase in zinc dose level and
subsequent elevation in serum zinc levels, indicating that
increasing zinc dose levels is one of the means to
achieve elevated serum zinc levels. Unfortunately, in
some patients, it is difficult to ingest sufficient amounts
of zinc because of adverse events such as nausea.
Therefore, it is desirable to develop drug preparations
enabling easy intake of large amounts of zinc.
A limitation of the present study is the small sample
size. However, to date, there have been few reports on
the long-term clinical efficacy of zinc other than
short-term data. Therefore, we believe that the data in
the present study are important, and hopefully will lead
to further large-scale studies.
In conclusion, our results showed that administration
of zinc does not improve hepatocarcinogenesis. However,
a serum zinc level greater than 80 μg (1.22 μmol)/dL
after zinc supplementation might be a good predictor of
cancer-free survival.
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