Journal of Gastroenrerologyand Hepatology (1991) Suppl. 1 , 3 1-35

ADONIS 08 1593199100G95D

Epidemiology of hepatitis C virus in Japan: Role in chronic liver disease and hepatocellular carcinoma MICHITAMI YANO, HIROSHI YATSUHASHI, OSAMI INOUE AND MICHIAKI KOGA Institute for Clinical Research, Nagasaki Chuo National Hospital, Nagasaki, Japan



The recent isolation by Choo et al. of the genome of hepatitis C virus (HCV), the causative agent of parenterally transmitted non-A, non-B hepatitis, has greatly advanced the characterization of the main agents that cause viral hepatitis in humans. Sero-epidemiological studies based on the detection of antibodies against C100-3, which is located in the non-structural region of the HCV polyprotein, suggest that this virus is the cause of most cases of post-transfusion non-A, non-B This review integrates what is known about HCV in Japan, its role in chronic liver disease and hepatocellular carcinoma (HCC) and the prognosis and treatment of chronic hepatitis C.


PREVALENCE OF ANTI-HCV AMONG BLOOD DONORS IN JAPAN Since November 1989, all blood donors in Japan have been screened for anti-HCV as well as for HBsAg. The anti-HCV positive rate is correlated with age, as depicted in Table 1. Older people have higher positivity. On the basis of this data it has been calculated that there are about 1.7 million antiHCV positive people in Japan. The frequency of HCV antibodies in blood donors has been reported as 1.2% in the USA and 0.9% in Italy, 0.7% in France and 0.4% in Germany.6 In Japan the rate is 1.4%, which is a little higher than in other developed countries (Table 1).

The Ministry of Health and Welfare has estimated that there are about 2 million cases of liver disease in Japan each year. In acute sporadic hepatitis, hepatitis A accounts for about 37%, hepatitis B for 28% and hepatitis C for 13% of cases. Hepatitis C accounts for 76% of cases of acute post-transfusion hepatitis and, in chronic hepatitis, hepatitis C accounts for 48% and hepatitis B for 40% of cases respectively (Fig. 1). In liver cirrhosis (LC), hepatitis C accpnts for 43% of cases: this is twice as much as hepatitis B. In HCC, hepatitis accounts for about 50% of cases, also twice as much as hepatitis B. In total, it is estimated that there are about 0.8 million HCV-related patients in Japan. HCV-related chronic liver disease is the most common form of viral hepatitis in Japan at any one time. Approximately 50% of chronic viral hepatitis is due to HCV infection in Japan.

AGE DISTRIBUTION OF HBV A N D HCV INFECTION The age-specific distribution of patients first diagnosed as having chronic hepatitis C and B is shown in Fig. 2. One hundred and twenty-four anti-HCV positive chronic hepatitis patients and 193 patients with both HBsAg and HBeAg positive chronic hepatitis were followed for an average of 8 years. Prevalence was found to be positively correlated with

Table 1 Estimated number of anti-HCV positive patients in Japan Age group (years)

Population Anti-HCV positive rate (YO) No. anti-HCV positive








26 033 0.00

8980 0.53 48

16024 0.97 151

19 792 1.52 300

17 372 1.55 276

32806 2.83 928

121007 1.41 1703


x 1000.

Correspondence: Prof. M. Yano, Nagasaki Chuo National Hospital, Institute for Clinical Research, Kubara 2-1001-1, Omura City, Nagasaki, Japan 856.

M . Yam et al.


age. In older age groups there was a high prevalence of chronic hepatitis C. This was the same distribution of HCV carrier state as in blood donors. In chronic hepatitis B, the incidence was highest in subjects who were 25-30 years old. Among younger patients with chronic hepatitis B, many underwent spontaneous improvement to a state of apparent cure. Therefore, the prevalence of hepatitis B in older people decreased. In contrast with this, spontaneous resolution of hepatitis C was less common, leaving a higher proportion of chronic carriers in older age groups.

RELATIONSHIP OF HCV EPITOPES T O CLINICAL INFECTION The so-called Chiron antigen, the C100-3 antigen, belongs to the non-structural (NS) 3-4 region in the RNA genome.’ Several other kinds of epitopes have now been reported, Acute sporadic hepatitis

TypeC hepatitis

Acute PTH

Chronic hepatitis
















such as C825 from the NS5 region and CP-9 in the core Each antigen-antibody system can be evaluated using various techniques. The core antigen-antibody system for HCV, the NS3 region, the NS4 and NS5 regions have all been studied. We examined the variance of these three antibody systems using six techniques available for their detection. We used three kinds of anti-C100-3 kits that had the same recombinant fusion polypeptide, but there were differences of coating between wells and beads,, and of assay between enzyme-linked immunosorbent assay and radio-immunoassay. KCL, the amino acids of which were mixed with those of the NS4 region, and C825 were developed as an enzyme immunoassay for detecting a specific anti-HCV (Mizuno, unpubl. data). A case of acute sporadic hepatitis C that developed to chronic hepatitis is shown in Fig. 3. Initially, there was a response to all the antibodies, such as anti-C100-3 arid antiNS5 region and anti-core region (CP-9). Later, however, anti-C100-3 disappeared while anti-core region (CP-9) and anti-NSS region (KCL) remained. After the disappearance of anti-C100-3, polymerase chain reaction (PRC) for HCVRNA was still positive. The important conclusion is that it can be very difficult to determine the diagnosis and course of hepatitis C with probes that are directed towards only one epitope of the HCV genome.


&I Total HCV-related patients

Figure 1 Estimated number of hepatitis virus related patients in Japan ( x 1000). LC: Liver cirrhosis, PTH: post-transfusion hepatitis.

DISTRIBUTION OF HCV EPITOPES IN PATIENTS WITH CHRONIC LIVER DISEASE One hundred and eighty-one cases of chronic liver disease have been tested for anti-HCV with three different epitopes of the RNA genome, such as core, NS3-4 region and NS5 region. Five different kit systems were used. Antibody against HCV core (CP-9) was the most sensitive test overall in these patients with chronic liver disease (Fig. 4). LE







40 50


Figure 2 Age-specific distribution of patients when first diagnosed as having chronic hepatitis, and their long-term prognosis: (a)liver cirrhosis, (0)clinical cure, (0)


Figure 3 A case of acute sporadic hepatitis C that developed to chronic hepatitis. In acute phase all the antibodies responded, but in chronic phase only anti-C100-3 disappeared while CP-9 and KCL remained. After the disappearance of anti-C100-3, PCR for HCVRNA was still positive. Top graph: (-) GOT, (---) GPT. Bottom graph: (-) ClOO EIA, (---) KCL, (--) CP-9.


Epidemiology of hepatitis C virus inJapan

In all, 90% of HCC cases were related to a hepatitis virus. It has been reported that 75% of a group of HCC patients from Spain and 65% of HCC patients from Italy were found to be anti-C100-3.10~''Kiyosawa also reported that anti-CIOO-3 was detected in 94% of a group of non-A, non-B HCC patients in Japan." It is concluded that HCV is an important factor associated with HCC.

COMPARISON OF COURSE OF CHRONIC HBV AND HCV INFECTION Figure 4 Rate of anti-HCV positivity in types of chronic liver disease (n -= 181). CHB: chronic hepatis B, CH NANB: chronic non-A non-B hepatitis, LCB: hepatitis B-related cirrhosis, LC NANB: non-A non-B hepatitis-related cirrhosis, HCC B: hepatocellular carcinoma-related hepatitis B, HCC NANB; hepatocellular carcinoma-related non-A non-B hepatitis, AIH: acute infectious cloo (EIA), (0) ~ 1 0 (RIA), 0 (0) p. (325, (0) KCL, hepatitis, (0) ).( CP-9.

A subgroup of 39 cases was tested by six techniques for anti-HCV and RNA, the latter with PCR (Fig. 5). The positivity rate for subjects tested by CP-9 was 90%. Of those with CP-9, 86% were positive by the PCR method. Only 10% of subjects were negative for CP-9. In a few negative cases for CP-9, sera were positive for HCV-RNA. Positivity was highest using anti-core, and correlation of the positive rate with anti-core and HCV-RNA was excellent. From these results, anti-core (CP-9) appears to be the most useful single diagnostic marker of HCV infection at this time.

The long-term prognoses of chronic hepatitis B and C are shown in Table 2. onehundred and fifty-five caSeS of of hepatitis B without chronic hepatitis c and 173 treatment were analysed. All cases were diagnosed with liver biopsy and were followed for an average of 8 years. All cases of chronic hepatitis B were positive for HBeAg in the period of initial diagnosis. The definition of clinical cure is confirmation of normal alanine aminotransferase values for more than 12 months and no progression to liver cirrhosis histologically. In addition, hepatitis B patients with clinical cure had to be continuously HBeAg negative for more than 12 months. Of 155 patients with chronic hepatitis C, 29.7% and 14.8% progressed to LC and HCC respectively (Table 2). Only 2.6% of hepatitis C patients improved to clinical cure. Of 173 hepatitis B patients, 17.3% and 4.6% progressed to LC and HCO respectively; 38.2% of hepatitis B patients improved to clinical cure. Chronic hepatitis B patients could be divided clearly into progressive or cure

HCV AND HEPATOCELLULAR CARCINOMA In the past 10 years, 333 cases of HCC have been diagnosed in the author's hospital. (Fig. 6). Combination tests with several HCV markers such as C100-3, KCL and CP-9 reveal that 50% of HCC is HCV-related and 36% is HBV-related.





30 Figure 6 Association of various hepatitis viruses wit' (n = 333).



Table 2 Long-term prognosis of chronic hepatitis t) Prognosis


+ -

+ -

+ -


+ -

+ -

+ -




Figure 5 Relationship between various anti-HCV assay results and PCR-. PCR (n = 39). (B) PCR+, (0)

LC HCC Clinical cure


and B

Type C (n = 155)

Type B (n = 173)

46 (29.7) 23 (14.8) 4 (2.6)

30 (17.3) 8 (4.6) 66 (38.2)

Percentages shown in parentheses.

M . Y a m et al.


Type C (n-23)

types during their course. In contrast, most chronic hepatitis C cases were progressive in the long term. Serial liver biopsies were carried out in 53 cases (Fig. 7). Chronic hepatitis was divided into four groups, depending on the stage of fibrosis. Chronic hepatitis C progressed to LC slowly in the initial stage and rapidly in the late stage. Chronic hepatitis B progressed to LC rapidly, in most cases within 3-4 years.





0 1 2 3 4 5 6 7 8 9 101112131415


Type B (n-30)

Twenty-six cases were treated with 6 million units of a or B interferon (IFN) daily for 8 weeks (Fig. 8). The total dose was 336 x lo6 unitdperson. Fourteen of the 26 cases (53%) responded completely (cure). In most cases of cure, aspartate aminotransferase levels fell just after starting the treatment. In patients successfully treated with IFN, the titre of anti-HCV (anti-C100-3) decreased remarkably, especially after the normalization of serum aminotransferase levels (Fig. 9). In a few cases, anti-HCV disappeared within 12 months. The titre of anti-HCV did not change in the group that did not respond to IFN treatment. Hence, the titre of anti-HCV may be useful for assessment of the response to IFN treatment for chronic hepatitic C.

0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 15


Figure 7 Relationship between follow-up period and the serial histological development of LC and HCC Grades 1-4: fibrosis of increasing extent, LC: Liver cirrhosis.

I F N 6 Miu/day




100 26











8d l w





3m 4m

5m 6 m


5m 6 m


Em 9m 10m l l m 12nl


IFN 6 Miu/day


P 300



26 -4s-1 0













2m 3m 4m



9m lorn I l m 12m

Follow-up period

Figure 8 Serum alanine aminotransferase (S-ALT) activities in the interferon responder (n = 14) and non-responder groups (n = 12).

Epidemiology of hepatitis C virus inJapan


IFN 6 Miulday

IFN 6 Miulday 10 000

Without treatment, the prognosis for chronic hepatitis C is much worse than that for chronic hepatitis B. Interferon therapy in chronic hepatitis C can frequently lead to clinical cure.


\ Non-eflective group (n-9)



: 1oc




Just after +6


0 Justafter +6


Figure 9 Course of anti-HCV (anti-C100-3) with IFN therapy in chronic hepatitis type C.

CONCLUSION There are an estimated 1.7 million HCV carriers and 0.8 million patients with hepatitis C related chronic liver disease in Japan. Antibody to HCV-RNA core region is the most sensitive and specific test to date for the diagnosis of HCV infection. The titre of anti-HCV reflects the replication of HCV. The hepatic necro-inflammatory changes of chronic hepatitis continue long-term in chronic hepatitis C carriers.

1. CHOOQ. L., Kuo G., WEINERA. J. et al. Isolation of cDNA clone derived from a blood-borne non-A, non-B viral hepalitis genome. Science 1989; 244: 359-62. 2. KUO G., CHOO Q. L., ALTER H. J. et al. An assay for circulating antibodies to a major etiologic virus of human nonA, non-B hepatitis. Science 1989; 244: 362-4. F., RASSHOFER R. et al. Anti3. ROCCENDORF M., DEINHARDT bodies to hepatitis C virus. Lancet 1989; ii: 324-5. H. W., LELIEP. N. et al. Anti4. VANDER POELC., REESINK hepatitis C antibodies and non-A, non-B post-transfusion hepatitis in the Netherlands. Lancet 1989; ii: 297-8. 5 . ALTERH. J., PURCELL R. H., SHIHJ. W. er al. Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N. Engl. 3. Med. 1989; 321: 1494-500. L. R., Kuo G. & HOUGH6. CHOOQ-L., WEINERA. J., OVERBY TON M. Hepatitis C virus: major causative agent of viral nonA, non-B hepatitis. Br. Med. Bull. 1990,46: 423-41. S. M. The virology of hepatitis C. 3. Gastroenterol. 7. FEINSTONE Hepatol. 1991; 6 (Suppl.): 26-8. K., SUGIMOTO H. et al. A cDNA clone 8. MAENOM., KAMINAKA closely associated with non-A, non-B hepatitis. Nucleic Acids Res. 1990; 18: 2685-9. 9. OKAMOTO H., OKADAS., SUCIYAMA Y. et al. The 5’-terminal sequence of the hepatitis C virus genome. 3pn. J . Exp. Med. 1990,601 167-77. 10. BRUIXJ., BARRERA J. M., CALVESX. et al. Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet 1989; ii: 1004-6. 11. COLOMBO M., Kuo G . , CHOOL. et al. Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma. Lancet 1989; ii: 1006-8. 12. KIYOSAWA K., SODEYAMA T., TANAKA E. et 01. Interrelationship of blood transfusion, non-A non-B hepatitis and hepatocellular carcinoma, analysis by detection of antibody to hepatitis C virus. Hepatology 1990; 12: 671-5.

Epidemiology of hepatitis C virus in Japan: role in chronic liver disease and hepatocellular carcinoma.

Journal of Gastroenrerologyand Hepatology (1991) Suppl. 1 , 3 1-35 ADONIS 08 1593199100G95D Epidemiology of hepatitis C virus in Japan: Role in chro...
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