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1494
The Long Term Efficacy of Glycyrrhizin in Chronic
Hepatitis C Patients
Yasuji Arase, M.D.
Kenji Ikeda, M.D.
Naoya Murashima, M.D.
Kazuaki Chayama, M.D.
Akihito Tsubota, M.D.
Isao Koida, M.D.
Yoshiyuki Suzuki, M.D.
Satoshi Saitoh, M.D.
Masahiro Kobayashi, M.D.
Hiromitsu Kumada, M.D.
BACKGROUND. Hepatocellular carcinoma (HCC) occurs in patients with hepatitis
Department of Gastroenterology, Tonanomon
Hospital, Tokyo, Japan.
9.2 years) and were given other herbal medicine (such as vitamin K). The patients
were retrospectively monitored, and the cumulative incidence of HCC and risk
factors for HCC were examined.
RESULTS. The 10th-year rates of cumulative HCC incidence for Groups A and B
were 7% and 12%, respectively, and the 15th-year rates were 12% and 25%. By Cox
C virus-RNA positive chronic liver disease. It is important to prevent HCC with
drug administration.
METHODS. A retrospective study was undertaken to evaluate the long term preventive effect of Stronger Neo-Minophagen C (SNMC) on HCC development. SNMC
is a Japanese medicine that is commonly administered to patients with chronic
hepatitis C to improve the serum alanine aminotransferase (ALT) level. Of 453
patients diagnosed with chronic hepatitis C retrospectively in the study hospital
between January 1979 and April 1984, 84 patients (Group A) had been treated with
SNMC; SNMC was given at a dose of 100 mL daily for 8 weeks, then 2–7 times a
week for 2–16 years (median, 10.1 years). Another group of 109 patients (Group
B) could not be treated with SNMC or interferon for a long period of time (median,
regression analysis, the relative risk of HCC incidence in patients not treated with
SNMC (Group B) was 2.49 compared with that of patients treated with SNMC
(Group A).
CONCLUSIONS. In this study, long term administration of SNMC in the treatment
of chronic hepatitis C was effective in preventing liver carcinogenesis. Cancer 1997;
79:1494–500. q 1997 American Cancer Society.
KEYWORDS: chronic hepatitis C, Stronger Neo-Minophagen C, glycyrrhizin, hepatocellular carcinoma.
H
Address for reprints: Yasuji Arase, M.D., Department of Gastroenterology, Tonanomon
Hospital, 2-2-2 Toranomon Minato-ku, Tokyo,
Japan.
Received September 23, 1996; revision received
December 9, 1996; accepted December 27,
1996.
epatocellular carcinoma (HCC) is one of the most common cancers in the world. Recently, greater than 80% of patients with HCC
were found to have RNA for the hepatitis C virus (HCV).1 The yearly
incidence of HCC in patients with HCV-RNA positive cirrhosis ranges
from 5 – 7% in Japan.1 – 3 Kiyosawa et al.1 reported that patients with
long term abnormal serum levels after transfusion had a high probability of histological aggravation as well as HCC. However, there are
few reports of chemopreventive studies of HCC.5 In this study, the
authors analyzed the chemopreventive action of Stronger Neo-Minophagen C (SNMC) in HCC patients. In Japan, SNMC has been used
in the form of an intravenous solution, comprised of 0.2% glycyrrhizin
(GL), 0.1% cysteine, and 2.0% glycine in physiologic solution. It is
made by dissolving GL (200 mg), cysteine (100 mg), and glycine (2 g)
in 100 mL of physiologic saline. GL is an aqueous extract of licorice
root (glycyrrhizae radix), which is antiallergic and has detoxicating
effects. As has been reported, the antiinflammatory mechanism of
q 1997 American Cancer Society
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W: Cancer
The Effect of Glycyrrhizin in Chronic Hepatitis C Patients/Arase et al.
SNMC is believed to be due to its protective effect on
the hepatic cellular membrane, which may explain its
ability to lower the serum transaminase level in patients with chronic hepatitis.6,7 Glycine prevents an
aldosteron-like action of GL8 and cysteine has been
found to be detoxicative as well as antiallergic through
cysteine conjugation in the liver.9 Therefore, SNMC
has been developed with the expectation of the joint
beneficial effect of these three components. Yamamoto et al.10 first treated patients with chronic hepatitis with SNMC and found a distinct improvement in
their ALT level. Suzuki et al.11 confirmed its ability to
suppress serum transaminase in patients with chronic
hepatitis in a randomized, double blind controlled
trial. Hino et al.12 and Yasuda et al.13 proved SNMC to
be useful in the improvement of transaminase and
liver histology. However, the long term effects of
SNMC on patients with chronic HCV have not been
confirmed. Therefore, in this study, the authors retrospectively analyzed the long term effects of SNMC on
patients with chronic HCV.
MATERIALS AND METHODS
Patients
The number of patients at the study hospital diagnosed with chronic hepatitis by laparoscopy and liver
biopsy between January 1979 and April 1984 was 874.
Of these 453 patients had the following criteria: 1) ALT
level more than twice the upper limit of the normal
range (50 IU) within 6 months before liver biopsy; 2)
anti-HCV (second-generation anti-HCV and enzymelinked immunoadsorbent assays) was positive in sera
preserved at 080 7C at the time of initial liver biopsy;
3) no corticosteroids, immunosuppressive agents, or
antiviral agents were administered 3 months before
liver biopsy; and 4) no hepatitis B surface antigens,
hepatitis virus DNA, or antinuclear antibodies were
detectable in the serum using radioimmunoassay and
spot hybridization. In these 453 patients, 84 patients
were treated with SNMC (Group A). SNMC was given
at a dose of 100 mL daily for 8 weeks and 2 – 7 times
a week for 2 to 16 years (median, 10.1 years). One
hundred nine patients were not treated with SNMC
(Group B) because there were no home health care
professionals available to give the intravenous injection. Therefore Group B patients were given other
herbal medicines (e.g., vitamin K) for 1 to 16 years
(median, 9.2 years) and did not receive corticosteroids,
immunosuppressive agents, or antiviral agents. The
remaining 210 patients were treated with a small
amount of SNMC, corticosteroids, or immunosuppressive agents. In this study, a comparison of Group A
with Group B was performed with regard to hepatocarcinogenesis.
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1495
Follow-up began on the first day of SNMC treatment in Group A patients and on the day of the liver
biopsy in Group B patients.
SNMC was prepared by Minophagen Pharmaceutical Company, Tokyo, Japan.
Patient Follow-Up
Clinical evaluation and biochemical and hematologic
tests were performed at monthly intervals. One patient
in Group A dropped out during the 7 years of followup. The remaining 83 patients continued to be treated
with SNMC. Sixteen patients in Group B were lost to
follow-up. Because the appearance of HCC was not
identified in these 17 patients, they considered as censored data in the statistical analysis.14 Deaths unrelated to HCC and patients who received treatment
with antiviral agents were also classified as withdrawals and were regarded as censored. Moreover, patients
treated with interferon (IFN) were regarded as withdrawals at the start of IFN treatment.
Moreover, the appearance rate of HCC was studied in 193 patients from both groups. Diagnosis of
HCC was made by the typical hypervascular characteristics observed on angiography, in addition to certain
features of computed tomography (CT) and ultrasonography. Microscopic examination by fine-needle biopsy was performed in patients whose angiograms did
not demonstrate a typical image of HCC. Pathologic
confirmation using surgically resected specimens was
made in 18 patients.
Examination of HCV Genotype
HCV genotype was determined by polymerase chain
reaction (PCR) with a mixed primer set derived from
nucleotide sequences of the NS5 region.15
Liver Histology
Liver histology of chronic hepatitis was classified from
the extent of fibrosis into three stages Stage I: periportal expansion; Stage II: portoportal septa; and Stage
III: portocentral linkage or bridging fibrosis.16
Statistical Analysis
Groups A and B were compared using the KruskalWallis test to assess differences in background factors;
P õ 0.05 was considered significant. ALT response to
SNMC was studied by the chi-square test. HCC appearance rates were analyzed by the log rank test. A
Cox proportional hazards model was used to analyze
the factors contributing to the HCC appearance rate;
factors examined included age, gender, histologic
findings, HCV genotype, transfusion, indocyanine
green retention rate at 15 (ICG R15) and SNMC admin-
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CANCER April 15, 1997 / Volume 79 / Number 8
TABLE 1
Profiles and Laboratory Data of the Patients at the Time of First Liver Biopsy
Parameters/Group
Group A (SNMC/; N Å 84)
Group B (SNMC0; N Å 109)
P value
Age (years)a
Gender (male/female)
Transfusion (//0)
Liver histology staging (I/II
or III)
HCV genotype (1b/2a or 2b)
ALT (IU)a
ICG R15 (%)a
47 (31–64)
73/11
39/45
48 (30–64)
92/17
48/61
0.579
0.833
0.801
51/33
60/16
200 (100–726)
14 (9–24)
61/48
62/21
186 (104–698)
15 (8–26)
0.507
0.486
0.422
0.767
SNMC: Stronger Neo-Minophagen C; HCV: hepatitis C virus; ALT: alanine aminotransferase; ICGR15: indocyanine green retention rate at 15 minutes.
a
Data are expressed as the median value (range).
TABLE 2
Average ALT Levels during Follow-Up Periods between Group A and
Group B
Average ALT
Normal
(ß50 IU)
Abnormal
(ú50 IU)
Group A (SNMC (/))
Group B (SNMC (0))
30 (35.7%)
7 (6.4%)
54 (64.3%)
102 (93.6%)
ALT: alanine aminotransferase; SNMC: Stronger Neo-Minophagen C.
istration. The analysis was made using Biomedical
Computer Program-p (BMDP).17,18
FIGURE 1. Cumulative hepatocellular carcinoma (HCC) appearance rate
of Group A with Stronger Neo-Minophagen C (SNMC) administration and
Group B without SNMC administration.
RESULTS
At the first liver biopsy, there was no significant differences between the two groups in age, gender ratio,
source of infection, stage of liver histology, HCV genotype, serum ALT level, and ICG R15 (Table 1).
Serum ALT Activity during the Follow-Up Period
Table 2 shows the average ALT levels during the follow-up period. The average ALT levels declined to normal levels range, (6 – 50 IU) in 30 (35.7%, of the 84
patients in Group A treated with SNMC, compared
with 7 (6.4%) of the 109 patients in Group B not treated
with SNMC. The trend toward stabilization of ALT in
Group A was statistically significant when compared
with that in Group B by the chi-square test (P Å
0.0000).
Cumulative HCC Appearance Rates
Figure 1 shows the cumulative HCC appearance rates
in both groups. The 10-year rates in Groups A and B
were 7% and 12%, respectively and the 15 year rates
were 12% and 25%, respectively. The HCC appearance
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rate in Group A was significantly lower than that in
Group B (P Å 0.0319).
Figure 2 shows the cumulative HCC appearance
rates based on the average ALT level for patients receiving SNMC administration. The HCC appearance
rate in the 30 patients with a normal ALT level was
slightly lower than that in the 54 patients with an elevated ALT level (P Å 0.08).
Figure 3 shows the cumulative HCC appearance
rates based on the average ALT level in Group B patients without SNMC administration. The HCC appearance rate in the 67 patients with an ALT level õ
100 IU was slightly lower than that in the 42 patients
with an ALT level ú 100 IU (P Å 0.054).
Figures 4 and 5 show the cumulative HCC appearance rates of patients based on histologic stage. In
patients with histologic Stage I, there was no significant difference between patients who did or did not
receive SNMC (P Å 0.34). However, patients with histologic Stages II and III, the HCC appearance rate in
the 33 patients treated with SNMC (Group A) was
W: Cancer
The Effect of Glycyrrhizin in Chronic Hepatitis C Patients/Arase et al.
1497
FIGURE 3. Cumulative hepatocellular carcinoma (HCC) appearance rate
FIGURE 2. Cumulative hepatocellular carcinoma (HCC) appearance rate
based on the average alanine aminotransferase level (ALT) after Stronger
based on the average alanine aminotransferase (ALT) level of Group B
without Stronger Neo-Minophagen C (SNMC) administration.
Neo-Minophagen C (SNMC).
FIGURE 5. Cumulative hepatocellular carcinoma (HCC) appearance rate
of patients with histologic Stages II and III.
FIGURE 4. Cumulative hepatocellular carcinoma (HCC) appearance rate
of patients with histologic Stage I.
slightly lower than that in the 48 patients who were
not treated with SNMC (Group B) (P Å 0.075).
Risk Factors for HCC
Cox regression analysis was performed with several
variables, including age, gender, history of blood
transfusion, histologic severity (staging), HCV genotype, ICG R15, and whether or not SNMC was administered.
Univariate analysis showed that the following four
factors significantly affected the cumulative HCC appearance rate in all patients: liver histology Stage I, II,
and III (P Å 0.0000), age (P Å 0.0052), SNMC administration (P Å 0.0319), and average ALT level (P Å 0.0437)
(Table 3). Because the variables were mutually correlated, multivariate Cox regression analysis was performed with the four statistically significant variables
in the model (Table 4). The relative risk for HCC ap-
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pearance rate in patients with Stage II or III liver histology was 13.82 compared with Stage I patients, the relative risk in patients who did not receive SNMC was
2.49 compared with patients treated with SNMC.
Side Effects of SNMC Therapy
Hypokalemia (serum potassium õ 3.7 mEq/mL) was
observed in 9 of the 84 patients (10.7%) in Group A. No
patients had a decrease õ3 mEq/mL, and the values
returned to the normal range (3.7 – 4.7 mEq/mL) after
administration of 150 mg/day of spironolactone. In
addition, an increase in blood pressure of ú160/90
mm Hg was observed in 3 of the 84 patients (3.6%),
but blood pressure returned to õ160/90 mm Hg after
the administration of 150 – 300 mg/day of spironolactone. Discontinuation of SNMC due to side effects did
not occur in any of the patients.
Causes of Death
During the observation period, 8 patients in Group A
(95%) died from causes including progression of HCC
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CANCER April 15, 1997 / Volume 79 / Number 8
TABLE 3
Factors Associated with HCC Appearance by Univariate Cox Regression Analysis
Factors
Category
Odds ratio
95% CI
P value
Liver histology (staging)
Stage I
Stage II, III
ß50 (normal)
ú50 (abnormal)
õ45
¢45
(/)
(0)
Female
Male
õ15
¢15
2a or 2b
1b
(/)
(0)
1
15.18
1
7.85
1
3.60
1
2.52
1
2.03
1
1.75
1
1.64
1
1.04
6.30–36.60
0.0000
1.04Ç59.74
0.0437
1.46Ç8.85
0.0052
1.08Ç5.87
0.0319
Average ALT
Age
SNMC
Gender
ICG R15 (%)
HCV genotype
Transfusion
0.185
0.175
0.354
0.918
HCC: hepatocellular carcinoma; CI: confidence interval; ALT: alanine aminotransferase; SNMC: Stronger Neo-Minophagen C; ICG RIS: indocyanine green retention rate at 15 minutes; HCV: hepatitis C virus.
TABLE 4
Factors Associated with HCC Appearance by Multivariate Cox Regression Analysis
Factors
Category
Odds ratio
95% CI
P value
Liver histology (staging)
Stage I
Stage II, III
(/)
(0)
1
13.82
1
2.49
5.4Ç34.5
0.0000
1.01Ç6.12
0.044
SNMC
HCC: hepatocellular carcinoma; CI: confidence interval; SNMC: Stronger Neo-Minophagen C.
in four patients, liver failure caused by cirrhosis in one
patient, and other diseases in three patients. In Group
B, 19 patients (17.4%) died from causes including progression of HCC in 13 patients, liver failure caused by
cirrhosis in 1 patient, and other disease in 5 patients.
DISCUSSION
Recently many authors have confirmed the therapeutic effect of IFN in patients with chronic HCV.19 – 23
However, the HCV clearance rates were more or less
constantly õ40 – 50%; the remaining cases had abnormal ALT levels after IFN therapy. In the study hospital
442 patients with positive HCV-RNA (serum samples
were stored at 080 7C until analysis by a reverse transcription nested PCR) were treated with human
lymphoblastoid IFN-a between January 1988 and April
1993.24 The total dose of IFN ranged from 336 MU to
624 MU. The HCC appearance rates in histologic
Stages I, II, and III were 0.1%, 0.6%, and 1.5% per year,
respectively.24 Conversely, in patients treated with
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SNMC the 10-year HCC appearance rates in histologic
Stages I, II, and III were 3%, and 13%, respectively.
Therefore, HCC appearance rates in patients treated
with IFN might be slightly lower than that of patients
with SNMC. However, many side effects occur during
therapy with IFN and IFN is expensive. Therefore,
when HCV-RNA positive patients are treated, whether
or not to use IFN therapy is an issue. In patients with
IFN-resistant HCV, treatments other than IFN are necessary to protect against histologic aggravation.
Finney and Somers25 reported on the antiinflammatory effects of glycyrrhizin, and SNMC has
been widely and effectively prescribed in Japan as
therapy for hepatitis. However, its pharmacologic actions have not been fully clarified. Watari7 reported
that SNMC had a protective effect on the hepatic cellular membrane. Ouchi et al.26 reported that glycyrrhizin
inhibited the production of prostaglandin E2 by activation of macrophages and the activity of phospholipase
A2 in arachinoic acid cascades in vitro.
W: Cancer
The Effect of Glycyrrhizin in Chronic Hepatitis C Patients/Arase et al.
In a randomized, double blind controlled trial, Suzuki et al.11 reported that SNMC was a useful agent for
improving serum ALT levels in patients with chronic
hepatitis, 133 patients were studied, with 67 receiving
40 mL SNMC daily and 66 a placebo for 4 weeks. A
significant improvement in liver function was noted
in the SNMC group (P õ 0.001). However, ALT were
slightly elevated again in the second week after the
medication was stopped. Hino et al.12 reported on the
effects of a large dose of SNMC (100 mL daily for 8
weeks) in 49 hospitalized patients with chronic hepatitis. All biopsy specimens obtained before and after
therapy were examined blindly by the same pathologist. Histologic improvement was observed in 35 patients (71%). However, these patients were examined
for only a few months. The long term effect of SNMC
administration for more than several years has not
been reported. In this study, the authors retrospectively investigated the long term effect of SNMC on
HCC appearance rates in patients with chronic HCV.
In the current study, the HCC appearance rate in 84
Group A patients who underwent long term treatment
with SNMC was significantly lower than that in the 109
Group B patients who were not treated with SNMC.
Nonrandomized retrospective studies may be not appropriate for the study of the efficacy of SNMC and
randomized prospective studies are best suited for this
purpose. However, in recent years, it is apparent that
the IFN has been widely employed for patients with
chronic HCV and has stabilized liver function in most
patients. Conversely, SNMC can be used in general for
patients with IFN-resistant HCV and in those with side
effects due to the IFN therapy. Moreover, patients with
chronic HCV cannot be treated with IFN or SNMC for
more than 10 years. Therefore, it will be important
that a randomized prospective study is begun to evaluate the long term preventive effect of SNMC on HCC
development.
Based on the results of the current study, the long
term administration of SNMC for chronic HCV was
considered to be effective in the reduction of liver carcinogenesis. The reason why SNMC administration reduces hepatocarcinogenesis is believed to be related
to the suppression of the necroinflammatory reaction
in the liver and the protection against histologic aggravation. In this study, the authors examined the cumulative cirrhosis appearance rates as well. The diagnosis
of cirrhosis was based on laboratory and clinical examinations, including ultrasonography, CT, and histologic examination. Seventy-one patients in Group A
and 81 patients in Group B were examined by repeated
liver biopsy. The 10-year rates of cumulative cirrhosis
in Groups A and B were 12% and 20%, respectively,
and the 15-year rates were 21% and 37%, respectively.
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1499
As a result, the cirrhosis appearance rate in Group A
was borderline, significantly lower than that in Group
B (P Å 0.07). Therefore, SNMC therapy could inhibit
the histologic aggravation of the liver in some chronic
HCV patients. Moreover, in patients treated with
SNMC, HCC appearance rates in patients with normal
ALT levels was lower than that of patients with abnormal ALT levels. The reduction in risk of HCC in the
SNMC group may be partly due to improvement in
the ALT level. Therefore, SNMC therapy, is believed to
help maintain ALT levels within normal limits.
The authors conclude that normalization of ALT
levels by long term administration of SNMC will assist
in protecting against hepatocarcinogenesis.
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