817
Hepatitis C Virus Infection in an Area Hyperendemic for Hepatitis B and Chronic Liver Disease: The Taiwan Experience Ding-Shinn Chen, George c. Kuo, Juei-Low Sung, Ming-Yang Lai, Jin-Chuan Sheu, Pei-Jer Chen, Pei-Ming Yang, Hsu-Mei Hsu, Mei-Hwei Chang, Chien-Jen Chen, Liang-Cheng Hahn, Qui-Lim Choo, Teh-Hong Wang, and Michael Houghton
From the Hepatitis Research Center, National Iaiwan University Hospital, the Graduate Institutes of Public Health and Clinical Medicine, Departments of Internal Medicine and Pediatrics, National Taiwan University College of Medicine, and Bureau of Disease Control, Department of Health, Executive JUan, 'Iaipei, and Hahn's Hospital, Iainan, Iaiwan, Republic of China; and Chiron Corporation, Emeryville, California
Chronic liver disease and hepatocellular carcinoma (HCC) are common disorders in humans and are frequently associated with hepatitis B virus (HBV) infection [1-4]. In Taiwan, cirrhosis of the liver and HCC are among the ten leading causes of death [5], and 80 %-85 % of patients with these conditions are positive for hepatitis B surface antigen (HBsAg) [4, 6, 7]. This strong association does not rule out factors or cofactors other than HBV in contributing to the occurrence or progression ofliver disease and HCC [4, 8-10]. Among these factors, the epidemiology of non-A, non-B (NANB) hepatitis closely resembles that of hepatitis B [11] and appears to cause exactly the same spectrum of chronic liver disease as HBV, which ranges from chronic persistent hepatitis to cirrhosis [12]. Further, patients who develop HCC subsequent to NANB hepatitis have been documented [10, 13-16]. Thus, it is imperative to clarify the role of NANB hepatitis virus(es) in chronic liver disease and HCC, even though HBV is undoubtedly the most important etiologic agent. Because of the lack of specific markers for NANB hepatitis, this kind of study has been difficult and a firm conclusion is currently impossible.
Received 12 January 1990; revised 19 April 1990. Grant support: Department of Health and National Science Council, Executive Yuan, Republic of China. G.c.K., Q.L.C., and M.H. are stockholders of the Chiron Corp. Reprints and correspondence: Dr. D. S. Chen, Hepatitis Research Center, National Taiwan University Hospital, 1 Chang-Te S1., Taipei, Taiwan 10016, Republic of China. The Journal of Infectious Diseases 1990;162:817-822 © 1990 by The University of Chicago. All rights reserved. 0022-1899/90/6204-0005$01.00
Recently, the major virus of parenterally acquired NANB hepatitis was identified, partly characterized [17], and designated hepatitis C virus (HCV). A specific assay for HCV circulating antibodies has been developed [18]. We investigated the presence of antibodies to HCV (anti-HCV) in patients with chronic liver disease, in groups at high risk for NANB hepatitis, and in healthy people in Taiwan, an area hyperendemic for chronic liver disease, HCC, and HBV infection [6].
Subjects and Methods Serum samples were studied from 1276 patients and subjects (table 1). These included 420 from volunteer blood donors before screening tests and 20 from volunteers eliminated as blood donors because of elevated levels of alanine aminotransferase (ALT; >45 lUll; median, 54; range, 46-107). Others were from 100 hemophiliacs (provided by Hemophiliac Service Center, National Taiwan University Hospital), 58 parenteral drug abusers (provided by the Correction Center for drug addicts [19]), 200 prostitutes (provided by the regulatory institutions for venereal disease control [20]), and 248 adult patients with chronic liver disease and HCC studied at National Taiwan University from 1984 to 1988. The latter group comprised 209 men and 39 women (mean age, 42 years; range, 18-76). The diagnosis of chronic liver disease was based on widely accepted clinical and histopathologic grounds [21]. Of the patients, 151 were positive and 97 were negative for HBsAg; however, all but 1 were positive for antibody to HBsAg or to hepatitis B core antigen (anti-HBc). Forty-six had chronic persistent hepatitis (20 HBsAg-positive), 75 had chronic active hepatitis (58 HBsAg-positive), 61 had hepatic cirrhosis (31 HBsAg-positive), and 66 had HCC (42 HBsAg-positive; table 2). In 45 of the 66 cases
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To assess the contribution of hepatitis C virus (HCV) in liver disease in Taiwan, antibody to HCY (anti-HCY) was studied by radioimmunoassay in 392 patients with chronic liver disease and in 440 healthy adults and 444 subjects at risk. The anti-HCY prevalence was 0.95% in 420 volunteer blood donors, 90% in 100 hemophiliacs, and 81% in 58 parenteral drug abusers. AntiHCY was present in 6 (7.7%) of 78 hepatitis B surface antigen (HBsAg)-positive and 28 (65%) of 43 HBsAg-negative patients with chronic hepatitis, 3 (10%) of 31 HBsAg-positive and 13 (43%) of 30 HBsAg-negative cirrhotics, and 7 (17%) of 42 HBsAg-positive and 15 (63%) of24 HBsAgnegative patients with hepatocellular carcinoma (HCC). An outbreak of non-A, non-B hepatitis revealed 18% of 57 patients to be positive for anti-HCY, and in 29 patients with posttransfusion hepatitis prospectively followed, 7 (24%) developed anti-HCY. Thus, HCY infection appears to playa relatively minor role in HBsAg-positive liver disease in Taiwan but is strongly associated with HBsAg-negative chronic liver disease and HCC. The infection is extremely common in hemophiliacs and parenteral drug abusers.
818
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Table 1. Prevalence of antibody to hepatitis C virus (anti-HCV) in different populations in Taiwan.
Subjects
Anti-HCY+
No. studied
No.
%
420 20
4 2
0.95 10.0
151 97 100 58 200 57 29 144
16 56 90 47 7 10 7 14
10.6 57.7 90.0 81.0 3.5 17.5 24.1 9.7
Volunteer blood donors With elevated ALT Chronic liver disease* HBsAg-positive HBsAg-negative Hemophiliacs Parenteral drug abusers Prostitutes Outbreak of non-A, non-B hepatitis Posttransfusion hepatitis (prospective study) Children with liver disease
=
hepatitis B surface
Results
of HCC, the state of the nontumorous liver could be studied, and 41 exhibited cirrhosis. Of the patients with HCC, 27 had tumors 45 lUll
(%)
No. studied
820
Chen et al.
fluid-transmitted hepatitis viruses, HBV and HDV [20]. Similar findings have been observed in patients diagnosed with sexually transmitted diseases [30]. This may result from less effective transmission ofHCV or reflect that the currently available first-generation anti-HCV assay is not sensitive enough to document all infections. Although anti-HCV was found to be common in chronic NANB hepatitis, the anti-HCV rate in posttransfusion NANB hepatitis in our study was relatively low (24 %). Although we assayed anti-HCV in serial serum samples ofthe affected patients, the follow-up period was ~6 months. It is therefore possible that the lower prevalence of anti-HCV is a result of inadequate sampling, because seroconversion of anti-HCV is uniformly delayed and may take as long as 1 year [34]. The relatively low anti-HCV prevalence may also be due to the less stringent criteria used to diagnose posttransfusion hepatitis in our prospective study. Also, most of the patients had subclinical and resolving HCV infection; only 6 of 29 had abnormal serum ALT activities 6 months after blood transfusion. Lower prevalence of anti-HCV in acute resolving posttransfusion NANB hepatitis has been reported [18, 27, 34]. In the self-limited outbreak ofNANB hepatitis, only one random serum sample from each patient was assayed and the prevalence was 18%. The increased frequency of anti-HCV strongly suggests the outbreak was actually hepatitis C. Unfortunately, the exact mode of transmission could not be identified [24]. HCV was also present in pediatric patients, but the overall prevalence was much lower than in adults. Whether perinatal transmission of HCV occurs remains controversial [31, 46]; however, the lower rates of HCV infection in children argue against such transmission as the important mode of HCV infection. Thus, HCV and HBV transmission differ [47]. In summary, we found HCV was second only to HBV as a cause of chronic liver disease and HCC in Taiwan. HCV infection was most prevalent in HBsAg-negative patients and was extremely common in hemophiliacs and parenteral drug abusers. These findings are similar to those reported in Western countries, and control of HCV infection is imperative in Taiwan. Acknowledgment We thank M. C. Shen for letting us study his hemophiliac patients; S.1. Lin Thaifor providing serum samples of volunteer blood donors; Y. Y. Chen, C. y. Shan, and M. S. Chuang for excellent clinical assistance, and Y. T. Chen for secretarial assistance.
References
1. Gitnick G. Chronic hepatitis: classification. In: Gitnick G, ed. Modern concepts of acute and chronic hepatitis. New York: Plenum, 1989:219-226 2. Galambos JT. Cirrhosis: pathogenesis. In: Galambos JT, ed. Cirrhosis. Philadelphia: W. B. Saunders, 1979:12-50
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to the occurrence ofHCC requires further investigation. However, a comparison of the age of HCC patients possessing both HBsAg and anti- HCV with that of patients possessing HBsAg only showed no statistically significant difference (55.1 ± 9.4 vs. 55.0 ± 10.5years, P>.5 by Student's ttest), but the number in the former group was small. Further comparison revealed the age of HBsAg-negative, anti-HCV-positive HCC patients to be f\JI0 years greater than that ofHBsAg-positive, anti-HCV-negative HCC patients (65.7 ± 7.4 vs. 55.0 ± 10.5 years, P < .05). These preliminary observations suggest that HCV does not accelerate the occurrence of HCC in HBV carriers, because the age of those HCC patients with both HBsAg and anti-HCV was not less than that of HCC patients with HBsAg only. Nevertheless, this should be interpreted with caution and requires further examination, because the biologic meaning of anti-HCV is still unclear and the number of cases studied to date is small. Although little is known about how HCV is associated with HCC, our study of HCC patients with nonneoplastic liver samples revealed that all of the anti-HCV-positive patients had coexisting cirrhosis in contrast to 87% of the anti-HCVnegative patients (data not shown). In HBsAg-positive patients with HCC in Taiwan, f\JI0%-15 % do not have coexisting cirrhosis [6]. This indicates that the hepatocarcinogenesis of HBV is not necessarily associated with a cirrhotic process [6, 37], as is true in hepadnavirus-induced HCC in woodchucks [38]. That all anti-HCV-positive HCCs were associated with coexisting cirrhosis suggests that HCV induces HCC indirectly; more specifically, that HCV causes HCC after inducing hepatic cirrhosis, a lesion long considered premalignant [39, 40]. Although HCV was found to be strongly associated with chronic liver disease and HCC, HBV remains the most important cause of these diseases in Taiwan and in many other areas of the world [3, 4, 6]. Efforts to effectively control HBV should continue [41, 42]. The HCV infection rate in hemophiliacs and parenteral drug abusers in this study was extremely high, and the anti-HCV prevalence was higher than that reported from Europe [26, 29]. In a separate study using the same serum samples, we observed a high prevalence (85 %) of hepatitis D virus (HDV) infection in the HBsAg-positive parenteral drug abusers in Taiwan [43]. Both HCV and HDV are transmitted by body fluids and the high rate of infection with these two viruses among this population indicates that the needles and syringes used by our parenteral drug abusers are heavily contaminated. If another virus such as the human immunodeficiency virus, which is still rare in Taiwan [44], was introduced into this community, the spread could be catastrophic. It is important to note that prostitutes also had a slightly higher anti-HCV prevalence (3.5 %). This is consistent with previous epidemiologic observations that NANB hepatitis can be transmitted sexually [11, 45], but the anti-HCV prevalence in prostitutes was still much lower than that of the other body
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Hepatitis C Virus Infection in Taiwan
24. Wang YF, Hsu NHM, Chen DS. Preliminary report on suspected nonA, non-B hepatitis-Chiayi County. Epidemiol Bull ROC 1987;3:69-71 25. Colombo M, Kuo G, Choo QL, Donato MF, Del Ninno E, Tommasini MA, Dioguardi N, Houghton M. Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma. Lancet 1989;2:1006-1008 26. Esteban 11, Esteban R, Viladomiu L, Lopez-Talavera JC, Gonzalez A, Hernandez JM, Roget M, Vargas V, Genesca J, Buti M, Guardia J, Houghton M, Choo QL, Kuo G. Hepatitis C virus antibodies among risk groups in Spain. Lancet 1989;2:294-297 27. van der Poel CL, Reesink HW, Lelie PN, Leentvaar-Kuypers A, Choo QL, Kuo G, Houghton M. Anti-hepatitis C antibodies and non-A, non-B posttransfusion hepatitis in the Netherlands. Lancet 1989;2:297-298 28. Kuhnl P, Seidl S, Stangel W, Beyer J, Sibrowski W, Flik 1. Antibody to hepatitis C virus in German blood donors [letter]. Lancet 1989;2:324 29. Roggendorf M, Deinhardt F, Rasshofer R, Eberle J, Hopf V, Moller B, Zachoval R, Pape G, Schramm W, Rommel F. Antibodies to hepatitis C virus [letter]. Lancet 1989;2:324-325 30. Hess G, Massing A, Rossol S, Schutt H, Clemens R, Meyer zum Biischenfelde KH. Hepatitis C virus and sexual transmission [letter]. Lancet 1989;2:987 31. Kamitsukasa H, Harada H, Yakura M, Fukuda A, Ohbayashi A, Saito I, Miyamura T, Choo QL, Houghton M, Kuo G. Intrafamilial transmission of hepatitis C virus [letter]. Lancet 1989;2:987 32. Bruix J, Barrera JM, Calvet X, Ercilla G, Costa J, Sanchez-Thpias JM, Ventura M, Vall M, Bruguera M, Bru C, Castillo R, Rodes 1. Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet 1989;2:1004-1006 33. Bortolotti F, Thgger A, Cadrobbi P, Crivellaro C, Ribero ML, Alberti A. Antibodies to hepatitis C virus in children with acute or chronic viral hepatitis [letter]. Lancet 1989;2:1162 34. Alter HJ, Purcell RH, Shih JW, Melpolder JC, Houghton M, Choo QL, Kuo G. Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N Engl J Med 1989;321:1494-1500 35. Hollinger FB, Alter HJ, Holland PV, Aach RD. Non-A, non-B hepatitis posttransfusion hepatitis in the Vnited States. In: Gerety RJ, ed. Non-A, non-B hepatitis. New York: Academic Press, 1981:49-70 36. Seeff LB, Dienstag JL. Transfusion-associated non-A, non-B hepatitis. Where do we go from here? Gastroenterology 1988;95:530-533 37. Chen DS, Sung JL. Cellular localization of hepatitis B surface antigen in the non-cirrhotic liver with hepatocellular carcinoma. Ital J Gastroenterol 1978;10:81-84 38. Popper H, Roth L, Purcell RH, Tennant BC, Gerin JL. Hepatocarcinogenicity of the woodchuck hepatitis virus. Proc Natl Acad Sci VSA 1987;84: 866-870 39. Kew MC, Popper H. Relationship between hepatocellular carcinoma and cirrhosis. Semin Liver Dis 1984;4:136-146 40. Johnson PJ, Williams R. Cirrhosis as the aetiology of hepatocellular carcinoma. J Hepatol 1987;4:140-147 41. Chen DS, Hsu NHM, Sung JL, Hsu TC, Hsu ST, Kuo YT, Lo KJ, Shih YT. A mass vaccination program in Taiwan against hepatitis B virus in infants of hepatitis B surface antigen-carrier mothers. JAMA 1987;257:2597-2603 42. Hsu HM, Chen OS, Chuang CH, Lu JCF, Jwo DM, Lee CC, Lu HC, Cheng SH, Wang YF, WangChen C, La KJ, Shih CJ, Sung JL. Efficacy of a mass hepatitis B vaccination program in Taiwan. Studies of 3464 infants of hepatitis B surface antigen-carrier mothers. JAMA 1988;260:2231-2235 43. Chen PJ, Chen OS, Chen CR, Chen YY, Chen Hsu HM, Lai MY, Sung JL. Delta infection in asymptomatic carriers of hepatitis B surface
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3. Munoz N, Bosch X. Epidemiology of hepatocellular carcinoma. In: Okuda K, Ishak KG, eds. Neoplasms of the liver. Tokyo: SpringerVerlag, 1987:3-19 4. Beasley RP. Hepatitis B virus: the major etiology of hepatocellular carcinoma. Cancer 1988;61:1942-1956 5. Lin TM, Tsu WT, Chen C1. Mortality of hepatoma and cirrhosis of liver in Taiwan. Br J Cancer 1986;54:969-976 6. Chen DS. Hepatitis B virus infection, its sequelae, and prevention in Taiwan. In: Okuda K, Ishak G, eds. Neoplasms of the liver. Tokyo: Springer-Verlag, 1987:71-80 7. Chen DS, Sung JL. Hepatitis B virus infection and chronic liver diseases in Taiwan. Acta Hepatogastroenterol 1978;25:423-430 8. Di Bisceglie AM, Rustgi VK, Hoofnagle JH, Dusheiko GM. Hepatocellular carcinoma. Ann Intern Med 1988;108:390-401 9. Thbor E. Hepatocellular carcinoma: possible etiologies in patients without serologic evidence of hepatitis B virus infection. J Med Virol 1989;27:1-6 10. Okuda K, Fujimoto I, Hanai A, Vrano Y. Changing incidence of hepatocellular carcinoma in Japan. Cancer Res 1987;47:4967-4972 11. Dienstag JL, Stevens CE, Szmuness W. The epidemiology of non-A, non-B hepatitis: emerging patterns. In: Gerety RJ, ed. Non-A, non-B hepatitis. New York: Academic Press, 1981:119-138 12. Rakela J, Redeker AG. Chronic non-A, non-B hepatitis. In: Gerety RJ, ed. Non-A, non-B hepatitis. New York: Academic Press, 1981:39-48 13. Resnick RH, Stone K, Antonioli D. Primary hepatocellular carcinoma following non-A, non-B posttransfusion hepatitis. Dig Dis Sci 1983;28:908-911 14. Gilliam JH, Geisinger KR, Richter JE. Primary hepatocellular carcinoma after chronic non-A, non-B posttransfusion hepatitis. Ann Intern Med 1984;101:794-795 15. Kiyosawa K, Akahane Y, Nagata A, Furuta S. Hepatocellular carcinoma after non-A, non-B posttransfusion hepatitis. Am J Gastroenterol 1984;79:777-781 16. Cohen EB, Gang DL, Zeldis JB. Primary hepatocellular carcinoma following nonspecific non-B hepatitis with tumor DNA negative for HBV DNA. Dig Dis Sci 1987;32:1428-1430 17. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989;244:359-362 18. Kuo G, Choo QL, Alter HJ, Gitnick G, Redeker AG, Purcell RH, Miyamura T, Dienstag JL, Alter HJ, Stevens CE, Tegtmeier GE, Bonino F, Colombo M, Lee WS, Kuo C, Berger K, Shuster JR, Overby LR, Bradley DW, Houghton M. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989;244:362-364 19. Hsu HM, Wang YF, Lo SH, Lee JCF, Chen JS, Chuang CH, Chen DS. Hepatitis D virus infection among intravenous drug addicts in Taiwan. In: Sung JL, Chen DS, eds. Viral hepatitis and hepatocellular carcinoma. Amsterdam: Excerpta Medica, 1990:23-31 20. Chen CJ, Hwang SJ, Fan KY, Chang SA, Chang YH, Wang YH, Wang SR, Liu WT, Liaw YF, Chai CY, Chang R, Ho M. Seroepidemiology of human T lymphotropic viruses and hepatitis viruses among prostitutes in Taiwan. J Infect Dis 1988;158:633-635 21. International Group. Acute and chronic hepatitis revisited. Lancet 1977;2:914-919 22. Chen DS, Sheu JC, Sung JL, Lai MY, Lee CS, Su CT, Tsang YM, How SW, Wang TH, YuJY, YangTH, Wang CY, Hsu CY. Small hepatocellular carcinoma-a clinicopathological study in thirteen patients. Gastroenterology 1982;83:1109-1119 23. Sheu JC, Sung JL, Chen DS, Lai MY, Wang IH, Yu JY, YangPM, Chuang CN, Yang PC, Lee CS, Hsu HC, How s« Early detection of hepatocellular carcinoma by real-time ultrasonography. A prospective study. Cancer 1985;56:660-666
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antigen: low prevalence of delta activity and effective suppression of hepatitis B virus replication. Hepatology 1988;8:1121-1124 44. Lin KT. Present status of human immunodeficiency virus infection in Taiwan. J Formosan Med Assoc 1987;86:467-473. 45. Alter MJ, Coleman PJ, Alexander WJ, Kramer E, Miller JK, Mandel E, Hadler SC, Margolis HS. Importance of heterosexual activity in the transmission of hepatitis B and non-A, non-B hepatitis. JAMA 1989;262:1201-1205
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46. Brotman B, Boehle W, Prince AM. Absence of perinatal transmission of blood-borne non-A, non-B hepatitis virus by chimpanzees with acute and chronic infection. J Moo Virol 1989;28:13-15 47. Stevens CE, Beasley RP, Tsui J, Lee We. Vertical transmission ofhepatitis B antigen in Taiwan. N Engl J Med 1975;292:771-774
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Hepatitis C Virus Infection in an Area Hyperendemic for Hepatitis B and Chronic Liver Disease: The Taiwan Experience Ding-Shinn Chen, George c. Kuo, Juei-Low Sung, Ming-Yang Lai, Jin-Chuan Sheu, Pei-Jer Chen, Pei-Ming Yang, Hsu-Mei Hsu, Mei-Hwei Chang, Chien-Jen Chen, Liang-Cheng Hahn, Qui-Lim Choo, Teh-Hong Wang, and Michael Houghton
From the Hepatitis Research Center, National Iaiwan University Hospital, the Graduate Institutes of Public Health and Clinical Medicine, Departments of Internal Medicine and Pediatrics, National Taiwan University College of Medicine, and Bureau of Disease Control, Department of Health, Executive JUan, 'Iaipei, and Hahn's Hospital, Iainan, Iaiwan, Republic of China; and Chiron Corporation, Emeryville, California
Chronic liver disease and hepatocellular carcinoma (HCC) are common disorders in humans and are frequently associated with hepatitis B virus (HBV) infection [1-4]. In Taiwan, cirrhosis of the liver and HCC are among the ten leading causes of death [5], and 80 %-85 % of patients with these conditions are positive for hepatitis B surface antigen (HBsAg) [4, 6, 7]. This strong association does not rule out factors or cofactors other than HBV in contributing to the occurrence or progression ofliver disease and HCC [4, 8-10]. Among these factors, the epidemiology of non-A, non-B (NANB) hepatitis closely resembles that of hepatitis B [11] and appears to cause exactly the same spectrum of chronic liver disease as HBV, which ranges from chronic persistent hepatitis to cirrhosis [12]. Further, patients who develop HCC subsequent to NANB hepatitis have been documented [10, 13-16]. Thus, it is imperative to clarify the role of NANB hepatitis virus(es) in chronic liver disease and HCC, even though HBV is undoubtedly the most important etiologic agent. Because of the lack of specific markers for NANB hepatitis, this kind of study has been difficult and a firm conclusion is currently impossible.
Received 12 January 1990; revised 19 April 1990. Grant support: Department of Health and National Science Council, Executive Yuan, Republic of China. G.c.K., Q.L.C., and M.H. are stockholders of the Chiron Corp. Reprints and correspondence: Dr. D. S. Chen, Hepatitis Research Center, National Taiwan University Hospital, 1 Chang-Te S1., Taipei, Taiwan 10016, Republic of China. The Journal of Infectious Diseases 1990;162:817-822 © 1990 by The University of Chicago. All rights reserved. 0022-1899/90/6204-0005$01.00
Recently, the major virus of parenterally acquired NANB hepatitis was identified, partly characterized [17], and designated hepatitis C virus (HCV). A specific assay for HCV circulating antibodies has been developed [18]. We investigated the presence of antibodies to HCV (anti-HCV) in patients with chronic liver disease, in groups at high risk for NANB hepatitis, and in healthy people in Taiwan, an area hyperendemic for chronic liver disease, HCC, and HBV infection [6].
Subjects and Methods Serum samples were studied from 1276 patients and subjects (table 1). These included 420 from volunteer blood donors before screening tests and 20 from volunteers eliminated as blood donors because of elevated levels of alanine aminotransferase (ALT; >45 lUll; median, 54; range, 46-107). Others were from 100 hemophiliacs (provided by Hemophiliac Service Center, National Taiwan University Hospital), 58 parenteral drug abusers (provided by the Correction Center for drug addicts [19]), 200 prostitutes (provided by the regulatory institutions for venereal disease control [20]), and 248 adult patients with chronic liver disease and HCC studied at National Taiwan University from 1984 to 1988. The latter group comprised 209 men and 39 women (mean age, 42 years; range, 18-76). The diagnosis of chronic liver disease was based on widely accepted clinical and histopathologic grounds [21]. Of the patients, 151 were positive and 97 were negative for HBsAg; however, all but 1 were positive for antibody to HBsAg or to hepatitis B core antigen (anti-HBc). Forty-six had chronic persistent hepatitis (20 HBsAg-positive), 75 had chronic active hepatitis (58 HBsAg-positive), 61 had hepatic cirrhosis (31 HBsAg-positive), and 66 had HCC (42 HBsAg-positive; table 2). In 45 of the 66 cases
Downloaded from http://jid.oxfordjournals.org/ at UQ Library on November 21, 2014
To assess the contribution of hepatitis C virus (HCV) in liver disease in Taiwan, antibody to HCY (anti-HCY) was studied by radioimmunoassay in 392 patients with chronic liver disease and in 440 healthy adults and 444 subjects at risk. The anti-HCY prevalence was 0.95% in 420 volunteer blood donors, 90% in 100 hemophiliacs, and 81% in 58 parenteral drug abusers. AntiHCY was present in 6 (7.7%) of 78 hepatitis B surface antigen (HBsAg)-positive and 28 (65%) of 43 HBsAg-negative patients with chronic hepatitis, 3 (10%) of 31 HBsAg-positive and 13 (43%) of 30 HBsAg-negative cirrhotics, and 7 (17%) of 42 HBsAg-positive and 15 (63%) of24 HBsAgnegative patients with hepatocellular carcinoma (HCC). An outbreak of non-A, non-B hepatitis revealed 18% of 57 patients to be positive for anti-HCY, and in 29 patients with posttransfusion hepatitis prospectively followed, 7 (24%) developed anti-HCY. Thus, HCY infection appears to playa relatively minor role in HBsAg-positive liver disease in Taiwan but is strongly associated with HBsAg-negative chronic liver disease and HCC. The infection is extremely common in hemophiliacs and parenteral drug abusers.
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Table 1. Prevalence of antibody to hepatitis C virus (anti-HCV) in different populations in Taiwan.
Subjects
Anti-HCY+
No. studied
No.
%
420 20
4 2
0.95 10.0
151 97 100 58 200 57 29 144
16 56 90 47 7 10 7 14
10.6 57.7 90.0 81.0 3.5 17.5 24.1 9.7
Volunteer blood donors With elevated ALT Chronic liver disease* HBsAg-positive HBsAg-negative Hemophiliacs Parenteral drug abusers Prostitutes Outbreak of non-A, non-B hepatitis Posttransfusion hepatitis (prospective study) Children with liver disease
=
hepatitis B surface
Results
of HCC, the state of the nontumorous liver could be studied, and 41 exhibited cirrhosis. Of the patients with HCC, 27 had tumors 45 lUll
(%)
No. studied
820
Chen et al.
fluid-transmitted hepatitis viruses, HBV and HDV [20]. Similar findings have been observed in patients diagnosed with sexually transmitted diseases [30]. This may result from less effective transmission ofHCV or reflect that the currently available first-generation anti-HCV assay is not sensitive enough to document all infections. Although anti-HCV was found to be common in chronic NANB hepatitis, the anti-HCV rate in posttransfusion NANB hepatitis in our study was relatively low (24 %). Although we assayed anti-HCV in serial serum samples ofthe affected patients, the follow-up period was ~6 months. It is therefore possible that the lower prevalence of anti-HCV is a result of inadequate sampling, because seroconversion of anti-HCV is uniformly delayed and may take as long as 1 year [34]. The relatively low anti-HCV prevalence may also be due to the less stringent criteria used to diagnose posttransfusion hepatitis in our prospective study. Also, most of the patients had subclinical and resolving HCV infection; only 6 of 29 had abnormal serum ALT activities 6 months after blood transfusion. Lower prevalence of anti-HCV in acute resolving posttransfusion NANB hepatitis has been reported [18, 27, 34]. In the self-limited outbreak ofNANB hepatitis, only one random serum sample from each patient was assayed and the prevalence was 18%. The increased frequency of anti-HCV strongly suggests the outbreak was actually hepatitis C. Unfortunately, the exact mode of transmission could not be identified [24]. HCV was also present in pediatric patients, but the overall prevalence was much lower than in adults. Whether perinatal transmission of HCV occurs remains controversial [31, 46]; however, the lower rates of HCV infection in children argue against such transmission as the important mode of HCV infection. Thus, HCV and HBV transmission differ [47]. In summary, we found HCV was second only to HBV as a cause of chronic liver disease and HCC in Taiwan. HCV infection was most prevalent in HBsAg-negative patients and was extremely common in hemophiliacs and parenteral drug abusers. These findings are similar to those reported in Western countries, and control of HCV infection is imperative in Taiwan. Acknowledgment We thank M. C. Shen for letting us study his hemophiliac patients; S.1. Lin Thaifor providing serum samples of volunteer blood donors; Y. Y. Chen, C. y. Shan, and M. S. Chuang for excellent clinical assistance, and Y. T. Chen for secretarial assistance.
References
1. Gitnick G. Chronic hepatitis: classification. In: Gitnick G, ed. Modern concepts of acute and chronic hepatitis. New York: Plenum, 1989:219-226 2. Galambos JT. Cirrhosis: pathogenesis. In: Galambos JT, ed. Cirrhosis. Philadelphia: W. B. Saunders, 1979:12-50
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to the occurrence ofHCC requires further investigation. However, a comparison of the age of HCC patients possessing both HBsAg and anti- HCV with that of patients possessing HBsAg only showed no statistically significant difference (55.1 ± 9.4 vs. 55.0 ± 10.5years, P>.5 by Student's ttest), but the number in the former group was small. Further comparison revealed the age of HBsAg-negative, anti-HCV-positive HCC patients to be f\JI0 years greater than that ofHBsAg-positive, anti-HCV-negative HCC patients (65.7 ± 7.4 vs. 55.0 ± 10.5 years, P < .05). These preliminary observations suggest that HCV does not accelerate the occurrence of HCC in HBV carriers, because the age of those HCC patients with both HBsAg and anti-HCV was not less than that of HCC patients with HBsAg only. Nevertheless, this should be interpreted with caution and requires further examination, because the biologic meaning of anti-HCV is still unclear and the number of cases studied to date is small. Although little is known about how HCV is associated with HCC, our study of HCC patients with nonneoplastic liver samples revealed that all of the anti-HCV-positive patients had coexisting cirrhosis in contrast to 87% of the anti-HCVnegative patients (data not shown). In HBsAg-positive patients with HCC in Taiwan, f\JI0%-15 % do not have coexisting cirrhosis [6]. This indicates that the hepatocarcinogenesis of HBV is not necessarily associated with a cirrhotic process [6, 37], as is true in hepadnavirus-induced HCC in woodchucks [38]. That all anti-HCV-positive HCCs were associated with coexisting cirrhosis suggests that HCV induces HCC indirectly; more specifically, that HCV causes HCC after inducing hepatic cirrhosis, a lesion long considered premalignant [39, 40]. Although HCV was found to be strongly associated with chronic liver disease and HCC, HBV remains the most important cause of these diseases in Taiwan and in many other areas of the world [3, 4, 6]. Efforts to effectively control HBV should continue [41, 42]. The HCV infection rate in hemophiliacs and parenteral drug abusers in this study was extremely high, and the anti-HCV prevalence was higher than that reported from Europe [26, 29]. In a separate study using the same serum samples, we observed a high prevalence (85 %) of hepatitis D virus (HDV) infection in the HBsAg-positive parenteral drug abusers in Taiwan [43]. Both HCV and HDV are transmitted by body fluids and the high rate of infection with these two viruses among this population indicates that the needles and syringes used by our parenteral drug abusers are heavily contaminated. If another virus such as the human immunodeficiency virus, which is still rare in Taiwan [44], was introduced into this community, the spread could be catastrophic. It is important to note that prostitutes also had a slightly higher anti-HCV prevalence (3.5 %). This is consistent with previous epidemiologic observations that NANB hepatitis can be transmitted sexually [11, 45], but the anti-HCV prevalence in prostitutes was still much lower than that of the other body
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Hepatitis C Virus Infection in Taiwan
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