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Population-based study of hepatitis C virus infection and hepatocellular carcinoma in western Japan
Hepatology Research 23 (2002) 18 – 24
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Population-based study of hepatitis C virus infection and hepatocellular carcinoma in western Japan Ikuko Wada, Toshiya Hara *, Susumu Kajihara, Toshihiko Mizuta, Iwata Ozaki, Akitaka Hisatomi, Kyosuke Yamamoto Department of Internal Medicine, Internal Medicine, Nabeshima, Saga 849 -8501, Japan Received 19 February 2001; received in revised form 27 June 2001; accepted 17 September 2001
Abstract Hepatitis C virus (HCV) infection is a major health problem in Japan. This infection is highly prevalent in subjects with chronic liver disease and is strongly associated with hepatocellular carcinoma. Epidemiological studies conducted by the Japanese Ministry of Health and Welfare showed that the mortality rate associated with hepatocellular carcinoma (HCC) was high in several prefectures in western Japan. In 1990, Saga Prefecture on the island of Kyushu in western Japan reported the highest HCC related mortality rate. Here, we report the results of a population-based survey in Saga Prefecture, where prevalence of HCV infection and mortality rate of HCC was assessed in the general population. From 1992 to 1997, the prevalence of HCV infection was assessed in the general population of 47 districts in Saga Prefecture. Among the 161 307 subjects (52 590 men, 108 357 women, older than 30 years) examined, 13 129 (8.1%) reacted positively to HCV antibody (anti-HCV). The prevalence of HCV-Ab reactivity was highest in subjects over 60 years of age. Reactivity increased from 3.6% in subjects 30 – 49 years old to 11% in those \ 50 years old. Highly significant differences were observed among the 45 districts in seropositive rates for anti-HCV, with the range being from 0.8 to 20.0%. We evaluated the association between the prevalence of anti-HCV reactivity and age-adjusted death rate from HCC in the general population of these districts, and detected a significant association (Pearson’ s correlation coefficient =0.721, PB 0.0001, Y =1.86X+ 16.1). In conclusion, these observations indicated that the outbreak of HCV in this area was a major cause of HCC in the population. © 2002 Published by Elsevier Science B.V. Keywords: Correlation study; Population-based study; Hepatitis C virus; Hepatitis C virus antibody; Hepatocellular carcinoma; Mortality; Japan
1. Introduction
* Corresponding author. Tel.: +81-952-31-6511; fax: + 81952-34-2017. E-mail address: [email protected] (T. Hara).
Hepatitis C virus (HCV) infection is a major health problem in Japan. It is highly prevalent in subjects with chronic liver disease and strongly associated with hepatocellular carcinoma [1,2]. More than 80% of patients with HCC suffer from
1386-6346/02/$ - see front matter © 2002 Published by Elsevier Science B.V. PII: S 1 3 8 6 - 6 3 4 6 ( 0 1 ) 0 0 1 6 1 - 9
I. Wada et al. / Hepatology Research 23 (2002) 18–24
HCV infection, and 10– 15% of patients with HCC suffer from hepatitis B virus (HBV) in Japan [3– 5]. Approximately, 150 million people in Japan are HCV carriers [6]. The age-adjusted mortality rate from HCC has increased over the past decades in Japan, and in 1995 it became the third leading cause of death in male cancer patients and the fourth in females [7]. Epidemiological studies conducted by the Japanese Ministry of Health and Welfare showed that the mortality rate from hepatocellular carcinoma (HCC) was high in several prefectures located in western Japan. Saga prefecture is located in northern Kyushu, in south-western Japan. The population of Saga Prefecture was 882 320 in 1995. In 1990, the incidence of HCC in this prefecture was reported to be 45.6 and 13.0 per 100 000 people for males and females, respectively, both of which were among the highest rates in Japan (Japanese Ministry of Health and Welfare) [8]. A committee for the prevention of liver diseases in Saga was set up in 1986. Its members include the Saga Prefectural Health Center, Saga Medical School and medical practitioners in the district. Preliminary epidemiological studies conducted by the Saga Prefectural Health Center revealed districts with especially high mortality rates due to HCC (H-districts) and others with relatively low rates (L-districts). Randomized studies showed an extremely high frequency of patients reactive to anti-HCV antibodies (10.8%) in the H-districts and a lower frequency (4.6%) in the L-districts. Although, there were no differences in the HBsAg positive rate between the two districts (1.8 vs. 1.7%). The high prevalence of HCV may be related to the high mortality rate from HCC in these districts [9]. Chronic HCV infection is generally asymptomatic and, therefore, goes undetected unless tested for specifically. An active population-based survey of anti-HCV reactivity is needed for prevention of HCC. From 1992 to 1997, the prevalence of HCV infection was assessed in about 28% of the general population of 47 districts in Saga prefecture (52 950 men, 108 357 women). We report herein the results of a population-based survey in Saga Prefecture where the prevalence of HCV infection and mortality
19
rate from HCC were assessed in the general population. 2. Patients and methods
2.1. Target population Except for public servants or employees of industries, inhabitants aged 30 and older were invited to participate in a mass screening for liver disorders offered by 47 out of 49 cities, towns and villages in Saga prefecture. From 1992 to 1997, the prevalence of HCV infection was assessed in the general population among the 161 370 subject (52 590 men, 108 357 women) 28% of the inhabitant. The age and sex distribution of the general population were similar throughout the 47 districts (Table 1).
2.2. HCV antibody Subject reactivity to HCV antibody (anti-HCV) was assessed by passive hemagglutination (PHA 2: Dinabott Tokyo, Japan). Antibody titer by agglutination using PHA can be expressed as 2n, using the end titer of a 2-fold serial dilution. Agglutination titers of 25 or higher by PHA signify positive reactivity according to the manufacturer’s instructions [10]. According to past studies [6] false positive rates of HCVAb in terms of HCV-RNA positivity were 27/34 (79.4%) when the titer of HCVAb was from 25 to 211. However, according to the same studies, false positive rates were 0/120 (0%) when the titer was higher than or equal to 212. Consequently, we classified HCVAb positive subjects into low-titer (from 25 to 211) and high-titer (higher than or equal to 212) groups. We believe that all subjects positive for the high-titer HCVAb possess actively replicating HCV, as compared with only a small of the subjects positive for the low-titer HCVAb. Among 13 172 subjects, we examined the prevalence of HCVAb positive subjects within the low-titer and high-titer groups in 1992. Since 1993, we examined the prevalence of HCVAb positive subjects. Agglutination titers of 25 or higher by PHA signify positive reactivity according to the manufacturer’s instructions.
I. Wada et al. / Hepatology Research 23 (2002) 18–24
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Table 1 The prevalence of HCV antibody positive rate and the age-adjusted death rate from HCC in 49 districts of Saga prefecutre Districts number
General population
Age 30 and older population
Positive for HCV antibody (%)
Death rate from HCC
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49
9443 6463 9868 19 633 11 752 22 124 7918 11 972 5622 24 007 1843 8525 9179 13131 7705 19 212 169 470 9297 59 824 11 564 12 204 6502 1670 34 870 7210 33 441 11 245 19 306 79 638 13 809 5299 10 613 9498 20 236 17 584 8493 5935 6397 7484 59 573 4831 10 533 10 665 7539 9019 2726 9334 8746 9590 882 544
5889 3945 21 870 12 003 7724 14 001 5080 7848 9351 16 153 1280 4812 5867 8893 5229 13 866 103 690 3783 36 733 7776 8102 4324 1133 22 759 4566 6334 7517 11 677 55 965 6382 3379 6566 6258 13 532 11 122 5772 4133 4385 4567 39 613 3231 6700 6688 4776 6269 1679 6274 6518 5943 143 811
28.3 28.2 20.3 18.9 17.4 16.7 14.6 13.6 11.6 11.4 11.3 11.0 10.3 9.6 8.3 8.1 8.0 7.5 6.9 6.9 6.7 6.6 6.3 5.2 5.1 5.1 4.8 4.7 4.7 4.7 4.6 4.4 4.4 4.4 4.3 4.1 4.0 4.0 3.5 3.3 3.2 2.7 2.6 2.2 2.0 1.9 1.1
65.6 46.1 31.2 49.8 29.3 53.6 42.8 33.4 19.2 26.8 22.3 35.1 33.5 23.2 31.4 24.5 28.7 20.5 42.6 39.9 25.9 25.1 15.5 19.7 18.8 25.7 11.9 23.7 25.3 17.0 19.2 21.0 14.7 16.5 20.1 13.9 20.7 28.6 20.4 21.1 13.8 13.3 21.1 18.3 18.2 4.4 20.8 21.0 18.0 26.8
8.1
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Fig. 1. The age-adjusted death rate from HCC increased from 1984 to 1995 in Saga prefecture and throughout Japan. There was a significant difference between males and females.
2.3. The mortality rate from HCC The mortality rate from HCC was assessed according to the age-adjusted death rate from HCC, averaged for 1984– 1995.
2.4. Statistical analysis Correlations between the age-adjusted death rate and anti-HCV reactivity were assessed using Pearson’s correlation coefficient at a significance level of P B0.05. All other statistical analyses were performed by 2 test; a P value of B0.05 was considered significant.
3. Results The age-adjusted death rate from HCC increased from 1984 to 1995. A significant difference was observed between males and females. In 1995, the age-adjusted death rate from HCC was 50 in males and 12 in females (Fig. 1).
Among the 161 307 subjects examined, 13 129 (8.1%) reacted positively to anti-HCV. Results from male subjects did not differ significantly from female subjects (8.8 vs. 7.8%). Reactivity increased from 3.3% in subjects 30– 49 years old to 10.1% in those \ 50 years old. (Fig. 2) The anti-HCV seropositive rate among the 47 districts, ranged from 0.8 to 20.0%. In 12 districts, the anti-HCV seropositive rate was over 10%. The age-adjusted death rate from HCC in the 49 districts ranged from 4.4 to 65.6 per 100 000 people (Table 1). We evaluated the relationship between anti-HCV reactivity and age-adjusted death rate from HCC in the general population of all 47 districts and found a significant correlation (Pearson’s correlation coefficients 0.721, P B0.0001, Y= 1.86X + 16.1) (Fig. 3). We examined the prevalence of HCVAb positive subjects in the low-titer and high-titer groups. In 13 172 subjects, the positive rate for a low titer of HCVAb was 5.6% (735) whereas the positive rate for a high titer of HCVAb was 7.8% (1029). These results suggested that approximately 60% of HCVAb positive subjects were HCV-RNA positivity. A significant difference was observed be-
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I. Wada et al. / Hepatology Research 23 (2002) 18–24
Fig. 2. Age -specific prevalence of anti-HCV reactivity in Saga prefecture, Japan. The prevalence of anti-HCV reactivity was highest among subjects over 50 years old.
tween male and female subjects in the positive rate for both a low titer and high titer of HCVAb (P B 0.001) (Table 2).
4. Discussion Approximately, 1.5 million people in Japan are HCV carriers. [10] The age-adjusted mortality rate from HCC has increased over the past decades in Japan and Saga prefecture (Fig. 1). Chronic HCV infection is generally asymptomatic and, therefore, goes undetected unless tested for specifically. An active population-based survey of anti-HCV reactivity is needed for prevention of HCC. The present study presents the results of the first mass screening for HCV infection in an area with a high prevalence of HCC. The rate of anti-HCV reactivity among the present subjects (8.1%) and especially the high seropositive rate in one of the prefectural districts (20.0%) were considerably higher than those of all blood donors in Japan were (1.1%) [6]. There have been several reports on outbreaks of HCV in isolated areas in Japan [11,12]. From a cross-sectional study of a
district where HCV infections were extraordinarily endemic, we established that the significant risk factors for HCV transmission were blood transfusion, surgical intervention, acupuncture therapy [13]. We found that similar strains of HCV genotype 1b was detected about 90% of patients infected with HCV in endemic area [14].
Fig. 3. Correlation between the prevalence of anti-HCV reactivity and age-adjusted mortality rate from HCC in the 148 958 subjects (Pearson’s correlation coefficient= 0.721, P B 0.0001).
I. Wada et al. / Hepatology Research 23 (2002) 18–24
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Table 2 The prevalence of HCVAb positive subjects in the low-titer and high-titer groups Reactivity to HCV antibody (anti-HCV)
Males Females Total
4591 8581 13 172
Negative
Positive
Low-titer groups
High-titer groups
3962 7446 11 408
629 (13.7%) 1135 (13.2%) 1764 (13.4%)
225 (4.9%)a 510 (5.9%)a 735 (5.6%)
404 (8.8%)a 625 (7.3%)a 1029 (7.8%)
PB0.001 2 test. We classified HCVAb positive subjects into low-titer (from 25 to 211) and high titer (higher than or equal to 212) groups. There was a significant difference between male and female subjects in the positive ratio titer of HCVAb. a
There results indicate an increased transmission of similar strains of HCV as a result of nosocomial infection. We evaluated the relationship between antiHCV reactivity and age-adjusted death rate from HCC in the general population of the districts and found a significant correlation (Pearson’s correlation coefficient = 0.721, P B 0.0001; Y = 1.86X + 16.1) (Fig. 3). The significant correlation between anti-HCV reactivity and age-adjusted death rate from HCC indicated that an outbreak of HCV was a major cause of mortality in HCC patients in Saga Prefecture, Japan. Epidemiological studies conducted by the Japanese Ministry of Health and Welfare demonstrated that the mortality rate from HCC was the highest in Saga Prefecture in 1990 [7]. These results suggested that an HCV epidemic was a major cause of HCC-related mortality in Japan. The prevalence of HCV-Ab reactivity was highest in subjects over 60 years of age. Reactivity increased from 3.3% in subjects 30– 49 years old to 10.1% in those \ 50 years old (Fig. 2). Most HCV-infected persons are over 50 years of age. The age-adjusted mortality rate from HCC has increased over the past decades. These findings indicated that an HCV epidemic occurred in Saga Prefecture during the past period prior to the study. Thus, HCC associated with HCV infection is likely to decrease during the next 10– 20 years as HCV infected people between 30 and 49 years of age at the time of study reach an age at which complications of chronic liver disease typically occur. In contrast, in the US, about 2.7 million people are chronically infected with HCV. Sixty-
five percent of the present populations with HCV infection were 30–49 years old. People who use illegal drugs or engage in high-risk sexual behavior account for the majority of those with HCV infection [15]. Most HCV-infected persons are younger than 50 years of age. Thus, the burden of disease associated with HCV infection is likely to increase during the next 10–20 years. In 1995, the age-adjusted death rate from HCC was 50 in males and 12 in females (Fig. 1). The gap between the risk in males and females may be possibly associated with smoking habits or alcohol habits [16– 19] or sex hormone [20,21]. We previously examined the interactive effect modification between viral infections and life-style habits on the risk of hepatocellular carcinoma (HCC) in a community-based prospective study in this area [22]. An interaction between of HBsAg status and history of cigarette smoking, HBsAg status and history of alcohol consumption, hightiter HCVAb status and history of cigarette smoking, and high-titer HCVAb status and a history of alcohol consumption were all significantly associated with the risk of contracting HCC. We examined the prevalence of 1764 HCVAb positive subjects low-titer and high-titer groups in 1992 (Table 2). The prevalence in the low-titer groups was 42%, whereas, it was 58% in the high-titer groups in the 1764 HCVAb positive subjects. We concluded that all subjects positive for the hightiter HCVAb possess actively replicating HCV, as compared with only a small percentage of the subjects positive for the low-titer HCVAb [6]. These results suggested that approximately 60% of HCVAb positive subjects were HCV-RNA pos-
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I. Wada et al. / Hepatology Research 23 (2002) 18–24
itive. We estimated that about 27 000 people are HCV carriers in this area. In male subjects, the positive rate for a high titer of HCVAb was 8.8%, whereas it was 7.3% in female subjects. There were significant differences between male and female subjects in the positive rate for a high titer of HCVAb (P B0.001). We concluded that this result represents one of the of risk factors of developing HCC in males and females, including eating habits and life style. In conclusion, the present findings suggested that an outbreak of HCV in small isolated areas was a major cause of HCC-related mortality in Saga prefecture Japan and a more active screening policy is required for prevention of HCC. In addition, we need to develop more effective therapies for persons infected with HCV. References [1] Nishioka K, Watanabe J, Furuta S, Tanaka E, Suzuki H, Iino S, Tsuji T, et al. Antibody to the hepatitis C virus in acute and chronic liver diseases in Japan. Liver 1991;11:65 – 70. [2] Nishioka K, Watanabe J, Furuta S, Tanaka E, Iino S, Suzuki H, Tsuji T, et al. A high prevalence of antibody to the hepatitis C virus in patients with hepatocellular carcinoma in Japan. Cancer 1991;67:429 – 33. [3] Tanaka K, Hirohata T, Koga S, Sugimachi K, Kanematsu T, Ohryohji F, Nawata H, et al. Hepatitis C and Hepatitis B in the etiology of hepatocellular carcinoma in the Japanese population. Cancer Res 1991;51:2842 –7. [4] Yuki N, Hayashi N, Kasahara A, Hagiwara H, Katayama K, Fusamoto H, Kamada K. Hepatitis B virus markers and antibodies to hepatitis C virus in Japanese patients with hepatocellular carcinoma. Dig Dis Sci 1992;37:65 – 72. [5] Kato Y, Nakata K, Omagari K, Furukawa R, Kusumoto Y, Mori I, Tajima H, et al. Risk of hepatocellular carcinoma in patients with cirrhosis in Japan. Cancer 1994;74:2234 – 8. [6] Watanabe J, Matsumoto C, Fujimura T, Shimada H, Yoshizawa H, Okamoto H, Iizuka, et al. Predictive value of screening tests for persistent hepatitis C virus infection evidence by viraemia. Vox Sang 1993;65:199 –203. [7] Health and Welfare Statistics Association. Trend of national public health. Kosei-no-Shihyo 1997;44:433 – 4 in Japanese. [8] Statistics and Information Department, Minister’s Secretariat, Ministry of Health and Welfare ed. Age-Adjusted Death Rates by Prefecture. Special Report on Vital Statistics. Kousei Toukei Kyoukai 1992: 100 – 103 (in Japanese). [9] Setoguchi Y, Yamamoto K, Ozaki I, Fujio N, Kariya T, Sakai T, Fujii S, et al. Prevalence of chronic liver disease
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and anti-HCV antibodies in different districts of Saga, Japan. Gastroenterologia Japonica 1991;26:157 – 61. Iino S, Koike K, Yasuda K, Hino K, Sainokami S, Suzuki H, Akahane K, et al. Passive hemagglutination (PHA) second generation assay system for HCV related antibody. Prog Med 1991;11:1911 – 21. Ito S, Ito M, Cho M, Shimotono K, Tajima K. Massive seroepidemiological study of hepatitis C virus: clustering of carriers on the southwest coast of Tsushima Japan. Jpn J Cancer Res 1991;82:1 – 3. Kiyosawa K, Tanaka E, Sodeyama T, Yoshizawa K, Yabe K, Furuta K, Imai H, et al. Transmission of hepatitis C in an isolated area in Japan: community-acquired infection. Gastroenterology 1994;106:1596 – 602. Mori M, Inutsuka H, Wada I, Yamamoto K, Honda M, Naramoto J. Factors associated with hepatitis C virus transmission in an area of high incidence of hepatic cancer in Japan. Hepatol Res 1998;10:17 – 26. Hara T, Setoguchi Y, Kajihara S, et al. Phylogenetic tree-based epidemiological analysis of hepatitis C virus transmission in a region of Japan with a high prevalence of infection. J Gastroenterol Hepatol 1996;11:641 – 5. Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, Kaslow RA, et al. The prevalence of Hepatitis C virus infection in the United States, 1988 through 1994. New Engl J Med 1999;341:556 – 62. Yu MW, You SL, Chang AS, Lu SN, Liaw YF, Chen CJ, et al. Association between hepatitis C virus antibodies and hepatocellular carcinoma in Taiwan. Cancer Res 1991;51:5621 – 5. Ikeda K, Saitoh S, Koida I, Arase Y, Tsubota H, Chayama K, Kunada H, Kawanishi M. A multivariate analysis of risk factors for hepatocellular carcinogenesis. A prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 1993;18:47 – 53. Chiba T, Matsuzaki Y, Abei M, Shaoda J, Tanaka N, Osuga T, Aikawa T. The role of previous hepatitis B virus infection and heavy smoking in hepatitis C virus-related hepatocellular carcinoma. Am J Gastroenterol 1996;91:1195 – 203. Donato F, Tagger A, Chiesa R, Ribero ML, Tomasoni V, Fasola M, Gelatti U, Portera G, Boffetta P, Nardi G. Hepatitis B and C virus infection, alcohol drinking, and hepatocellular carcinoma. A case-control study in Italy. Hepatology 1997;26:579 – 84. Yu MW, Chen CJ. Elevated serum testosterone levels and risk of hepatocellular carcinoma. Cancer Res 1993;53:790 – 4. Yuan JM, Ross RK, Stanczyk FZ, Govindarajan S, Gao YT, Hendarson BE, Yu MC. A cohort study of serum testosterone and hepatocellular carcinoma in Shanghai, China. Int J Cancer 1995;63:491 – 3. Mori M, Hara M, Yamamoto K, Hara T, Honda M, Naramoto J. Prospective study of hepatitis B and C viral infections, cigarette smoking, alcohol consumption, and other factors associated with hepatocellular carcinoma risk in Japan. Am J Epidemiol 2000;151:131 – 9.
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Population-based study of hepatitis C virus infection and hepatocellular carcinoma in western Japan Ikuko Wada, Toshiya Hara *, Susumu Kajihara, Toshihiko Mizuta, Iwata Ozaki, Akitaka Hisatomi, Kyosuke Yamamoto Department of Internal Medicine, Internal Medicine, Nabeshima, Saga 849 -8501, Japan Received 19 February 2001; received in revised form 27 June 2001; accepted 17 September 2001
Abstract Hepatitis C virus (HCV) infection is a major health problem in Japan. This infection is highly prevalent in subjects with chronic liver disease and is strongly associated with hepatocellular carcinoma. Epidemiological studies conducted by the Japanese Ministry of Health and Welfare showed that the mortality rate associated with hepatocellular carcinoma (HCC) was high in several prefectures in western Japan. In 1990, Saga Prefecture on the island of Kyushu in western Japan reported the highest HCC related mortality rate. Here, we report the results of a population-based survey in Saga Prefecture, where prevalence of HCV infection and mortality rate of HCC was assessed in the general population. From 1992 to 1997, the prevalence of HCV infection was assessed in the general population of 47 districts in Saga Prefecture. Among the 161 307 subjects (52 590 men, 108 357 women, older than 30 years) examined, 13 129 (8.1%) reacted positively to HCV antibody (anti-HCV). The prevalence of HCV-Ab reactivity was highest in subjects over 60 years of age. Reactivity increased from 3.6% in subjects 30 – 49 years old to 11% in those \ 50 years old. Highly significant differences were observed among the 45 districts in seropositive rates for anti-HCV, with the range being from 0.8 to 20.0%. We evaluated the association between the prevalence of anti-HCV reactivity and age-adjusted death rate from HCC in the general population of these districts, and detected a significant association (Pearson’ s correlation coefficient =0.721, PB 0.0001, Y =1.86X+ 16.1). In conclusion, these observations indicated that the outbreak of HCV in this area was a major cause of HCC in the population. © 2002 Published by Elsevier Science B.V. Keywords: Correlation study; Population-based study; Hepatitis C virus; Hepatitis C virus antibody; Hepatocellular carcinoma; Mortality; Japan
1. Introduction
* Corresponding author. Tel.: +81-952-31-6511; fax: + 81952-34-2017. E-mail address: [email protected] (T. Hara).
Hepatitis C virus (HCV) infection is a major health problem in Japan. It is highly prevalent in subjects with chronic liver disease and strongly associated with hepatocellular carcinoma [1,2]. More than 80% of patients with HCC suffer from
1386-6346/02/$ - see front matter © 2002 Published by Elsevier Science B.V. PII: S 1 3 8 6 - 6 3 4 6 ( 0 1 ) 0 0 1 6 1 - 9
I. Wada et al. / Hepatology Research 23 (2002) 18–24
HCV infection, and 10– 15% of patients with HCC suffer from hepatitis B virus (HBV) in Japan [3– 5]. Approximately, 150 million people in Japan are HCV carriers [6]. The age-adjusted mortality rate from HCC has increased over the past decades in Japan, and in 1995 it became the third leading cause of death in male cancer patients and the fourth in females [7]. Epidemiological studies conducted by the Japanese Ministry of Health and Welfare showed that the mortality rate from hepatocellular carcinoma (HCC) was high in several prefectures located in western Japan. Saga prefecture is located in northern Kyushu, in south-western Japan. The population of Saga Prefecture was 882 320 in 1995. In 1990, the incidence of HCC in this prefecture was reported to be 45.6 and 13.0 per 100 000 people for males and females, respectively, both of which were among the highest rates in Japan (Japanese Ministry of Health and Welfare) [8]. A committee for the prevention of liver diseases in Saga was set up in 1986. Its members include the Saga Prefectural Health Center, Saga Medical School and medical practitioners in the district. Preliminary epidemiological studies conducted by the Saga Prefectural Health Center revealed districts with especially high mortality rates due to HCC (H-districts) and others with relatively low rates (L-districts). Randomized studies showed an extremely high frequency of patients reactive to anti-HCV antibodies (10.8%) in the H-districts and a lower frequency (4.6%) in the L-districts. Although, there were no differences in the HBsAg positive rate between the two districts (1.8 vs. 1.7%). The high prevalence of HCV may be related to the high mortality rate from HCC in these districts [9]. Chronic HCV infection is generally asymptomatic and, therefore, goes undetected unless tested for specifically. An active population-based survey of anti-HCV reactivity is needed for prevention of HCC. From 1992 to 1997, the prevalence of HCV infection was assessed in about 28% of the general population of 47 districts in Saga prefecture (52 950 men, 108 357 women). We report herein the results of a population-based survey in Saga Prefecture where the prevalence of HCV infection and mortality
19
rate from HCC were assessed in the general population. 2. Patients and methods
2.1. Target population Except for public servants or employees of industries, inhabitants aged 30 and older were invited to participate in a mass screening for liver disorders offered by 47 out of 49 cities, towns and villages in Saga prefecture. From 1992 to 1997, the prevalence of HCV infection was assessed in the general population among the 161 370 subject (52 590 men, 108 357 women) 28% of the inhabitant. The age and sex distribution of the general population were similar throughout the 47 districts (Table 1).
2.2. HCV antibody Subject reactivity to HCV antibody (anti-HCV) was assessed by passive hemagglutination (PHA 2: Dinabott Tokyo, Japan). Antibody titer by agglutination using PHA can be expressed as 2n, using the end titer of a 2-fold serial dilution. Agglutination titers of 25 or higher by PHA signify positive reactivity according to the manufacturer’s instructions [10]. According to past studies [6] false positive rates of HCVAb in terms of HCV-RNA positivity were 27/34 (79.4%) when the titer of HCVAb was from 25 to 211. However, according to the same studies, false positive rates were 0/120 (0%) when the titer was higher than or equal to 212. Consequently, we classified HCVAb positive subjects into low-titer (from 25 to 211) and high-titer (higher than or equal to 212) groups. We believe that all subjects positive for the high-titer HCVAb possess actively replicating HCV, as compared with only a small of the subjects positive for the low-titer HCVAb. Among 13 172 subjects, we examined the prevalence of HCVAb positive subjects within the low-titer and high-titer groups in 1992. Since 1993, we examined the prevalence of HCVAb positive subjects. Agglutination titers of 25 or higher by PHA signify positive reactivity according to the manufacturer’s instructions.
I. Wada et al. / Hepatology Research 23 (2002) 18–24
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Table 1 The prevalence of HCV antibody positive rate and the age-adjusted death rate from HCC in 49 districts of Saga prefecutre Districts number
General population
Age 30 and older population
Positive for HCV antibody (%)
Death rate from HCC
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49
9443 6463 9868 19 633 11 752 22 124 7918 11 972 5622 24 007 1843 8525 9179 13131 7705 19 212 169 470 9297 59 824 11 564 12 204 6502 1670 34 870 7210 33 441 11 245 19 306 79 638 13 809 5299 10 613 9498 20 236 17 584 8493 5935 6397 7484 59 573 4831 10 533 10 665 7539 9019 2726 9334 8746 9590 882 544
5889 3945 21 870 12 003 7724 14 001 5080 7848 9351 16 153 1280 4812 5867 8893 5229 13 866 103 690 3783 36 733 7776 8102 4324 1133 22 759 4566 6334 7517 11 677 55 965 6382 3379 6566 6258 13 532 11 122 5772 4133 4385 4567 39 613 3231 6700 6688 4776 6269 1679 6274 6518 5943 143 811
28.3 28.2 20.3 18.9 17.4 16.7 14.6 13.6 11.6 11.4 11.3 11.0 10.3 9.6 8.3 8.1 8.0 7.5 6.9 6.9 6.7 6.6 6.3 5.2 5.1 5.1 4.8 4.7 4.7 4.7 4.6 4.4 4.4 4.4 4.3 4.1 4.0 4.0 3.5 3.3 3.2 2.7 2.6 2.2 2.0 1.9 1.1
65.6 46.1 31.2 49.8 29.3 53.6 42.8 33.4 19.2 26.8 22.3 35.1 33.5 23.2 31.4 24.5 28.7 20.5 42.6 39.9 25.9 25.1 15.5 19.7 18.8 25.7 11.9 23.7 25.3 17.0 19.2 21.0 14.7 16.5 20.1 13.9 20.7 28.6 20.4 21.1 13.8 13.3 21.1 18.3 18.2 4.4 20.8 21.0 18.0 26.8
8.1
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Fig. 1. The age-adjusted death rate from HCC increased from 1984 to 1995 in Saga prefecture and throughout Japan. There was a significant difference between males and females.
2.3. The mortality rate from HCC The mortality rate from HCC was assessed according to the age-adjusted death rate from HCC, averaged for 1984– 1995.
2.4. Statistical analysis Correlations between the age-adjusted death rate and anti-HCV reactivity were assessed using Pearson’s correlation coefficient at a significance level of P B0.05. All other statistical analyses were performed by 2 test; a P value of B0.05 was considered significant.
3. Results The age-adjusted death rate from HCC increased from 1984 to 1995. A significant difference was observed between males and females. In 1995, the age-adjusted death rate from HCC was 50 in males and 12 in females (Fig. 1).
Among the 161 307 subjects examined, 13 129 (8.1%) reacted positively to anti-HCV. Results from male subjects did not differ significantly from female subjects (8.8 vs. 7.8%). Reactivity increased from 3.3% in subjects 30– 49 years old to 10.1% in those \ 50 years old. (Fig. 2) The anti-HCV seropositive rate among the 47 districts, ranged from 0.8 to 20.0%. In 12 districts, the anti-HCV seropositive rate was over 10%. The age-adjusted death rate from HCC in the 49 districts ranged from 4.4 to 65.6 per 100 000 people (Table 1). We evaluated the relationship between anti-HCV reactivity and age-adjusted death rate from HCC in the general population of all 47 districts and found a significant correlation (Pearson’s correlation coefficients 0.721, P B0.0001, Y= 1.86X + 16.1) (Fig. 3). We examined the prevalence of HCVAb positive subjects in the low-titer and high-titer groups. In 13 172 subjects, the positive rate for a low titer of HCVAb was 5.6% (735) whereas the positive rate for a high titer of HCVAb was 7.8% (1029). These results suggested that approximately 60% of HCVAb positive subjects were HCV-RNA positivity. A significant difference was observed be-
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Fig. 2. Age -specific prevalence of anti-HCV reactivity in Saga prefecture, Japan. The prevalence of anti-HCV reactivity was highest among subjects over 50 years old.
tween male and female subjects in the positive rate for both a low titer and high titer of HCVAb (P B 0.001) (Table 2).
4. Discussion Approximately, 1.5 million people in Japan are HCV carriers. [10] The age-adjusted mortality rate from HCC has increased over the past decades in Japan and Saga prefecture (Fig. 1). Chronic HCV infection is generally asymptomatic and, therefore, goes undetected unless tested for specifically. An active population-based survey of anti-HCV reactivity is needed for prevention of HCC. The present study presents the results of the first mass screening for HCV infection in an area with a high prevalence of HCC. The rate of anti-HCV reactivity among the present subjects (8.1%) and especially the high seropositive rate in one of the prefectural districts (20.0%) were considerably higher than those of all blood donors in Japan were (1.1%) [6]. There have been several reports on outbreaks of HCV in isolated areas in Japan [11,12]. From a cross-sectional study of a
district where HCV infections were extraordinarily endemic, we established that the significant risk factors for HCV transmission were blood transfusion, surgical intervention, acupuncture therapy [13]. We found that similar strains of HCV genotype 1b was detected about 90% of patients infected with HCV in endemic area [14].
Fig. 3. Correlation between the prevalence of anti-HCV reactivity and age-adjusted mortality rate from HCC in the 148 958 subjects (Pearson’s correlation coefficient= 0.721, P B 0.0001).
I. Wada et al. / Hepatology Research 23 (2002) 18–24
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Table 2 The prevalence of HCVAb positive subjects in the low-titer and high-titer groups Reactivity to HCV antibody (anti-HCV)
Males Females Total
4591 8581 13 172
Negative
Positive
Low-titer groups
High-titer groups
3962 7446 11 408
629 (13.7%) 1135 (13.2%) 1764 (13.4%)
225 (4.9%)a 510 (5.9%)a 735 (5.6%)
404 (8.8%)a 625 (7.3%)a 1029 (7.8%)
PB0.001 2 test. We classified HCVAb positive subjects into low-titer (from 25 to 211) and high titer (higher than or equal to 212) groups. There was a significant difference between male and female subjects in the positive ratio titer of HCVAb. a
There results indicate an increased transmission of similar strains of HCV as a result of nosocomial infection. We evaluated the relationship between antiHCV reactivity and age-adjusted death rate from HCC in the general population of the districts and found a significant correlation (Pearson’s correlation coefficient = 0.721, P B 0.0001; Y = 1.86X + 16.1) (Fig. 3). The significant correlation between anti-HCV reactivity and age-adjusted death rate from HCC indicated that an outbreak of HCV was a major cause of mortality in HCC patients in Saga Prefecture, Japan. Epidemiological studies conducted by the Japanese Ministry of Health and Welfare demonstrated that the mortality rate from HCC was the highest in Saga Prefecture in 1990 [7]. These results suggested that an HCV epidemic was a major cause of HCC-related mortality in Japan. The prevalence of HCV-Ab reactivity was highest in subjects over 60 years of age. Reactivity increased from 3.3% in subjects 30– 49 years old to 10.1% in those \ 50 years old (Fig. 2). Most HCV-infected persons are over 50 years of age. The age-adjusted mortality rate from HCC has increased over the past decades. These findings indicated that an HCV epidemic occurred in Saga Prefecture during the past period prior to the study. Thus, HCC associated with HCV infection is likely to decrease during the next 10– 20 years as HCV infected people between 30 and 49 years of age at the time of study reach an age at which complications of chronic liver disease typically occur. In contrast, in the US, about 2.7 million people are chronically infected with HCV. Sixty-
five percent of the present populations with HCV infection were 30–49 years old. People who use illegal drugs or engage in high-risk sexual behavior account for the majority of those with HCV infection [15]. Most HCV-infected persons are younger than 50 years of age. Thus, the burden of disease associated with HCV infection is likely to increase during the next 10–20 years. In 1995, the age-adjusted death rate from HCC was 50 in males and 12 in females (Fig. 1). The gap between the risk in males and females may be possibly associated with smoking habits or alcohol habits [16– 19] or sex hormone [20,21]. We previously examined the interactive effect modification between viral infections and life-style habits on the risk of hepatocellular carcinoma (HCC) in a community-based prospective study in this area [22]. An interaction between of HBsAg status and history of cigarette smoking, HBsAg status and history of alcohol consumption, hightiter HCVAb status and history of cigarette smoking, and high-titer HCVAb status and a history of alcohol consumption were all significantly associated with the risk of contracting HCC. We examined the prevalence of 1764 HCVAb positive subjects low-titer and high-titer groups in 1992 (Table 2). The prevalence in the low-titer groups was 42%, whereas, it was 58% in the high-titer groups in the 1764 HCVAb positive subjects. We concluded that all subjects positive for the hightiter HCVAb possess actively replicating HCV, as compared with only a small percentage of the subjects positive for the low-titer HCVAb [6]. These results suggested that approximately 60% of HCVAb positive subjects were HCV-RNA pos-
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itive. We estimated that about 27 000 people are HCV carriers in this area. In male subjects, the positive rate for a high titer of HCVAb was 8.8%, whereas it was 7.3% in female subjects. There were significant differences between male and female subjects in the positive rate for a high titer of HCVAb (P B0.001). We concluded that this result represents one of the of risk factors of developing HCC in males and females, including eating habits and life style. In conclusion, the present findings suggested that an outbreak of HCV in small isolated areas was a major cause of HCC-related mortality in Saga prefecture Japan and a more active screening policy is required for prevention of HCC. In addition, we need to develop more effective therapies for persons infected with HCV. References [1] Nishioka K, Watanabe J, Furuta S, Tanaka E, Suzuki H, Iino S, Tsuji T, et al. Antibody to the hepatitis C virus in acute and chronic liver diseases in Japan. Liver 1991;11:65 – 70. [2] Nishioka K, Watanabe J, Furuta S, Tanaka E, Iino S, Suzuki H, Tsuji T, et al. A high prevalence of antibody to the hepatitis C virus in patients with hepatocellular carcinoma in Japan. Cancer 1991;67:429 – 33. [3] Tanaka K, Hirohata T, Koga S, Sugimachi K, Kanematsu T, Ohryohji F, Nawata H, et al. Hepatitis C and Hepatitis B in the etiology of hepatocellular carcinoma in the Japanese population. Cancer Res 1991;51:2842 –7. [4] Yuki N, Hayashi N, Kasahara A, Hagiwara H, Katayama K, Fusamoto H, Kamada K. Hepatitis B virus markers and antibodies to hepatitis C virus in Japanese patients with hepatocellular carcinoma. Dig Dis Sci 1992;37:65 – 72. [5] Kato Y, Nakata K, Omagari K, Furukawa R, Kusumoto Y, Mori I, Tajima H, et al. Risk of hepatocellular carcinoma in patients with cirrhosis in Japan. Cancer 1994;74:2234 – 8. [6] Watanabe J, Matsumoto C, Fujimura T, Shimada H, Yoshizawa H, Okamoto H, Iizuka, et al. Predictive value of screening tests for persistent hepatitis C virus infection evidence by viraemia. Vox Sang 1993;65:199 –203. [7] Health and Welfare Statistics Association. Trend of national public health. Kosei-no-Shihyo 1997;44:433 – 4 in Japanese. [8] Statistics and Information Department, Minister’s Secretariat, Ministry of Health and Welfare ed. Age-Adjusted Death Rates by Prefecture. Special Report on Vital Statistics. Kousei Toukei Kyoukai 1992: 100 – 103 (in Japanese). [9] Setoguchi Y, Yamamoto K, Ozaki I, Fujio N, Kariya T, Sakai T, Fujii S, et al. Prevalence of chronic liver disease
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