Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, especially in sub-Saharan Africa and Southeast Asia.1, 2 HCC is estimated to have an incidence of between 250,000 and 1.2 million per year worldwide. Chronic hepatitis B virus (HBV) infection has been well documented to have a major role in the development of this cancer.1 Recently, hepatitis C virus (HCV) has been well established as the most significant etiologic agent for non-A, non-B hepatitis.3 HCV infection often progresses to chronic hepatitis or cirrhosis, which may be associated with HCC.4
The prevalence of antibodies to HCV (anti-HCV) in HCC patients varies considerably by region, from a low rate of 6.2% in Mozambique to a high rate of 75% in Spain.5, 6 The highest rates are found in southern Europe and Japan;6, 7 intermediate rates in Greece, Saudi Arabia, and Taiwan;8–10 and low rates (<20%) in the U.S., Africa, India, and other countries in the Far East.5, 11–13 Localized endemic areas of HCV have also been reported in Japan,14 Egypt,15 and Cameroon.16 In Taiwan, in contrast to an HBV carrier rate of 15–20% in the general population,17 the seropositivity rate of blood donors for anti-HCV is only 1%.18 In Taiwan as a whole, it has been reported that about 80% of the HCC cases were related to HBV infection17 and 32% were related to HCV infection.19 However, Paisha and Tzukuan townships (two townships in southern Taiwan) were reported to be both HBV and HCV-endemic areas, and HCV was reported to be the main cause of HCC in Tzukuan township.20 It is important to identify local HCV-endemic areas to keep HCV from spreading. It would be important to know the etiologic variations of HCC in different geographic areas in Taiwan. It would also be important to know the etiologic variations of HCC between southern and northern Taiwan. In this study, we evaluated the hepatitis B surface antigen (HBsAg) and anti-HCV status and surveyed the gender and age of patients with HCC from different geographic areas in Taiwan, compared the data on HCC patients from southern Taiwan with data on those from northern Taiwan, and tried to find other HCV endemic areas.
MATERIALS AND METHODS
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- MATERIALS AND METHODS
Two medical centers of the Chang Gung Memorial Hospital, Kaohsiung Medical Center in southern Taiwan and Linkou Medical Center in northern Taiwan, were selected as the study hospitals (Fig. 1). There are approximately 2500 beds for inpatients in Kaohsiung Medical Center, the biggest hospital in southern Taiwan, at which the patients are from all areas of southern Taiwan. There are approximately 3500 beds for inpatients in Linkou Medical Center, the biggest hospital in northern Taiwan, at which the patients are from all areas of northern Taiwan and part of southern Taiwan. At these two hospitals, patients receiving liver biopsy or operation for HCC are hospitalized. A total of 284 (232 males and 52 females) consecutive patients proven to have HCC cytologically, on biopsy, or surgically with available data from HBsAg and anti-HCV tests were recruited for this study. Their gender, age at the time of diagnosis, and place of residence (county or city) were abstracted from medical records. These patients were from all areas of Taiwan.
Figure 1. H1 represents Kaohsiung Medical Center, Chang Gung Memorial Hospital; H2 represents Linkou Medical Center, Chang Gung Memorial Hospital; and H3 represents God's Help Hospital. The shaded area represents southern Taiwan. All other areas represent northern Taiwan.
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There are 16 counties and 5 cities in Taiwan. In this study, areas south of Chiayi County (Chiayi County, Tainan County, Tainan City, Kaohsiung City, Kaohsiung County, Pingtung County, and Penghu County) were defined as southern Taiwan (Fig. 1). All other areas were therefore defined as northern Taiwan (Fig. 1). A total of 176 patients were from southern Taiwan and a total of 108 patients were from northern Taiwan. We compared the HCC patients from the southern areas with those from the northern areas to see if there were any trends in age, gender, and viral etiology (the prevalence of HBsAg and anti-HCV). We were also interested in finding out whether there were local geographic variations in the viral etiology of HCC. If the case number of any county or city was 20 or more for either gender, the viral etiology in these counties and cities was further analyzed. If a statistical difference of viral etiology existed, the etiology of HCC would be studied with data from regional hospitals.
HBsAg and anti-HCV were tested by radioimmunoassay (Abbott Laboratories, North Chicago) and by a second-generation enzyme immunoassay (Abbott), respectively. For statistical analyses, the Student t test, the chi-square test, the Fisher exact test, and a goodness-of-fit test were performed. A three-way analysis of variance and multiple logistic regression were also performed as multivariate analyses.
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- MATERIALS AND METHODS
Both HBV and HCV infections are important worldwide problems. In Taiwan, the HBV carrier rate is about 15–20% of the general population,17 and HCC ranks second among the causes of death due to malignancy. About 80% of patients with HCC in Taiwan have previously been reported to be positive for HBsAg.17 In our study, 66.9% of HCC patients were HBsAg positive. Chronic infection with HCV is also a risk factor for HCC.4 In Taiwan, 1% of blood donors are seropositive for anti-HCV.18 Thirty-two percent of HCC patients have previously been reported to be anti-HCV positive in Taiwan.19 In our study, 30.6% of HCC patients were anti-HCV positive.
In this study, the mean age of HCC patients who were HBsAg positive was 9 years younger than the mean age of patients who were HBsAg negative. This result agrees with that of a previous report.21 One of the reasons for this age difference is that in Taiwan, most of the HBV-related HCC patients are infected with HBV by vertical transmission,22 whereas most of the HCV-related HCC patients are infected with HCV in adulthood.23 In addition, our study showed that the age of HCC patients who were both HBsAg positive and anti-HCV positive was not statistically different from the age of those who were HBsAg positive and anti-HCV negative. Our results suggest that HCV infection does not accelerate the occurrence of HCC in HBV carriers. This result is compatible with a previous report.18
In our study, male HCC patients had a higher prevalence of HBsAg positivity than females (71.5% vs. 46.1%, P < 0.001), whereas females had a higher prevalence of anti-HCV positivity than males (44.2% vs. 27.7%, P = 0.019; Table 1). The male-to-female ratio was 4.5:1 for all recruited HCC patients (from Table 1). This ratio was lower than a previous report24 (8:1) but was compatible with another report.25 The male-to-female ratio was as high as 7:1 in HBsAg positive HCC (Table 1). This showed that, in Taiwan, male gender was an even more significant factor in HBV-related HCC. The reasons for the gender differences between HBV-related and HCV-related HCC patients are unclear. Some previous reports suggest that the possible factors contributing to the male predominance among HCC patients include the association with HBV, the higher proportion of male cirrhotics, smoking, and alcohol drinking.25, 26 However, the ratio was 2.8:1 for anti-HCV positive HCC because of the greater prevalence of anti-HCV positivity among females (Table 1). Of 190 HBsAg positive HCC patients, 13.2% were anti-HCV positive, whereas 66.0% of the 94 HBsAg negative HCC patients were anti-HCV positive (Table 1). HCV appeared to play a major role in HBsAg negative HCC. HCV infection appeared to play a relatively minor role in HBsAg positive HCC in Taiwan, which agreed with a previous report.18
There was no significant difference in the prevalence of either HBV or HCV among HCC patients between the southern and northern areas of Taiwan. However, the results from the Chang Gung Memorial Hospital in our study showed local geographic variations of HBV and HCV prevalence in Taiwan, such as in Chiayi County and Taipei County. In male HCC patients, the prevalence of anti-HCV in Chiayi County in southern Taiwan (52%) was significantly greater than that of Taiwan as a whole (27.6%) (P = 0.007), whereas the prevalence in Taipei County in northern Taiwan (8.7%) was significantly less (P = 0.041) (Table 2). We further analyzed HCC patients at a different referral hospital in Chiayi County, God's Help Hospital, where 54.3% of 35 HCC patients were anti-HCV positive. These data supported our observation that the prevalence of anti-HCV among HCC patients in Chiayi County was significantly higher than the prevalence in Taiwan as a whole. We pooled the 30 patients from Chang Gung Memorial Hospital in Chiayi County and the 35 from God's Help Hospital in Chiayi County, and of the total of 65 patients 55.4% were anti-HCV positive and 46.2% were HBsAg positive. This was significantly different from the 30.6% anti-HCV positive and 66.9% HBsAg positive in Taiwan as a whole (P < 0.001 and P = 0.002 respectively) (Table 3). These data indicated that in the Chiayi area, both HCV and HBV infection played important roles in HCC, and that HCV infection was predominant. In general, it may take 25–30 years for an HCV infection to cause HCC.27 There is a possibility, therefore, that HCV infection may have existed in the Chiayi area for a long time.
Hepatitis C is carried by about 0.5–2.0% of blood donors worldwide.3, 18, 28, 29 However, the prevalence is extremely high in some areas. For example, the rate is higher than 6% in Zaire,30 6% in regions of Saudi Arabia,31 and higher than 16% in isolated communities in Japan.32 HCV is most efficiently transmitted by large or repeated percutaneous exposures, such as transfusions, transplantation from an infected donor, or sharing of contaminated needles among injection drug users.33 The Center for Disease Control estimated that an average of 150,000 HCV infections occurred annually in the U.S. during the past decade. Only 6% of patients report a history of blood transfusion; 46% report parental drug use.34, 35 Persons with percutaneous, sexual, or household exposures account for approximately 60% of the cases of acute hepatitis C, but persons with no specific source for HCV infection continue to account for a large number of patients, and low socioeconomic level is associated with a substantial proportion of these patients.33 Other possible routes of HCV transmission include hemodialysis, perinatal exposure, and parental exposures in the health care setting. Sharing of hygiene items such as such as combs, razors, toothbrushes, and nail scissors has been proposed as a possible means of transmission.33, 36 Folk remedies, such as acupuncture and cutting the skin using nonsterilized knives, were also implicated.14
In a study of an HCV endemic area of Japan, the major route of transmission was iatrogenic contact with contaminated needles.37 The same transmission route was implicated in Chiayi County. Genotyping or nucleotide sequencing of HCV may elucidate the possible causes of HCV infection and possible transmission route38 in this area. It has been reported that superinfection with HCV increased the HBsAg clearance rates of HBV carriers.39, 40 The annual clearance rate of HBsAg in dual HBV and HCV infected patients was 2.08%, significantly higher than in HBV infection alone (0.43%).40 The early clearance of HBsAg in cases with dual HBV and HCV infection should be considered one factor in the reduction in the number of HBsAg-related HCC patients in the Chiayi area.
In the Chiayi area, patients with HCC who were older than 60 years were statistically more likely to have disease associated with HCV infection. In addition, patients who lived in the city were statistically more likely to be anti-HCV positive than patients who lived in the rural areas (Table 4). In the Chiayi area, modern medical facilities were first introduced into the city more than 3 decades ago, and then gradually into the rural areas. The people in the Chiayi area requested injections when they visited a doctor, and disposable needles and syringes were not popularly used until 15 years ago. Therefore, in this area the people in the city may have had an earlier and greater chance of receiving iatrogenic contamination of HCV and developing HCV-related HCC. This is compatible with a previous study.20 Other possible transmission routes need to be further investigated.
HCV-related HCC has recently been increasing in many countries, notably Japan.7, 41 However, HBV-associated HCC is being reduced to near-extinction in Japan, perhaps as a result of the vaccination program and improved living conditions. In Taiwan, the vaccination program has also reduced the HBV carrier rate and HCC rate in children.42 In the future, HBV-related HCC will be markedly reduced in adults, and HCV-associated HCC may increase as in Japan. Interferon may reduce the chance of, or delay the development of, both HCV-related and HBV-related HCC.43–47
Several localized HCV-endemic areas have been reported in the world.14–16, 20 In Taiwan, Paisha and Tzukuan townships were reported to be both HBV- and HCV-endemic areas; HCV is the main cause of HCC in Tzukuan township.20 In this hospital-based study from the two biggest hospitals in Taiwan (Kaohsiung Medical Center and Linkou Medical Center of Chang Gung Memorial Hospital), we identified HCV as the main cause of HCC in the Chiayi area and confirmed this at the biggest local hospital in that area, God's Help Hospital. Although the number of cases studied so far is small, the number is significant. Further confirmatory studies are being performed. Recently, Wang et al. found that in the Chiayi area, of 73 HCC patients, 53.4% were anti-HCV positive and 46.5% were HBsAg positive.48 The prevalence of anti-HCV among HCC patients in different geographic areas is worth studying. Prevention includes considering all anti-HCV or HCV-RNA positive people to be potentially infectious and preventing all the possible transmission routes mentioned previously in this article. Screening donor blood for anti-HCV has reduced posttransfusion hepatitis, as has reduction in the use of shared syringes and needles. After screening donor blood for anti-HCV, the rate of posttransfusion hepatitis fell 73% in the U.S.49 and Japan50 and fell from 9.6% to 1.9% in Spain.51 There are still several obstacles to the development of an effective vaccine against HCV. Currently, interferon alone or a combination of interferon and ribavirin is suggested for treating hepatitis C patients.52–55
In a localized area with a high prevalence of anti-HCV positive HCC patients, the prevalence of anti-HCV in the population of that entire area must be investigated. The possible transmission routes should be identified and blocked. The treatment of hepatitis C must be aggressive to reduce the chance of spreading the virus and generating new HCC.