Journal of Gastroenterology and Hepatology (1992) 7, 237-239
LIVER AND BILIARY Hepatitis C virus infection in chronic liver disease and hepatocellular carcinoma in Saudi Arabia MOHAMED ALI AL KARAWI,* SOHAIL SHARIQ,* ABDEL RAHMAN EL SHIEKH MOHAMED,* AWAD A. SAEEDt AND ABDUL MUTAAL MOHAMED AHMED. *Gastroenterology Division and tMicrobiology Division, Armed Forces Hospital, Riyadh, Saudi Arabia Abstract The prevalence of antibody to hepatitis C virus (HCV) was determined in 139 patients with chronic liver disease (CLD) and 42 patients with hepatocellular carcinoma (HCC) during one year at the Riyadh Military Hospital, Saudi Arabia. The anti-HCV was detected in 36 of 96 (37.5%) HBsAg-negative patients with chronic liver disease and six of 43 (13.9%) HBsAg-positive patients with chronic liver disease. In addition, 1 1 (42.3%)HBsAg-negative hepatocellular carcinoma patients and two of 16 (12.5°/~)HBsAg-positive hepatocellular patients had antibody to HCV. The anti-HCV prevalence was 1.5% in 4818 healthy blood donors and 1% in 385 antenatal patients. The overall HCV seropositivity of 30.4% in 181 liver disease patients (CLD and HCC) in Saudi Arabia is lower than that reported from European countries.
Key words: chronic liver disease, hepatitis C, hepatocellular carcinoma.
INTRODUCTION Non-alcoholic chronic liver disease is a frequent cause of significant morbidity and mortality in Saudi Arabia. Besides known microbial agents like hepatitis B virus4 and Schistosomu mansoni causing chronic liver disease in the Arab penninsula,’ it had been apparent for a number of years that another agent was responsible for a significant number of acute and chronic hepatitis. It remained elusive despite intensive effort for over a decade until a major breakthrough came when a portion of the genome of a non-A, non-B hepatitis virus designated as hepatitis C virus (HCV) was cloned in 1989,6 and a specific immunoassay for HCV antibodies (anti-HCV) was developed.’ Subsequently, antiHCV was reported in a high proportion of patients with post-transfusion chronic non-A, non-B hepatitis,* and more frequently in the general community in the absence of any prior history of transfusion.’ This article describes the prevalence of HCV infection in Saudi Arabia and its relation to chronic liver disease and hepatocellular carcinoma. For comparison with the normal population, the prevalence was studied in apparently healthy blood donors and antenatal women.
METHODS During one year (October 1989-October 1990), blood samples from 5384 patients and subjects were studied for anti-
Table 1 Prevalence of antibody to hepatitis C virus in different population groups
Subjects
No. studied
Anti-HCV n ‘YO
Volunteer blood donor Antenatal
4818 385
72 4
1.5 1
Total
5203
76
1.5
43 96
6 36
13.9 37.5
16 26
2 11
12.5 42.3
181
55
30.4
Chronic liver disease (n = 139) HBsAg positive HBsAg negative Hepatocellular carcinoma (n = 42) HBsAg positive HBsAg negative Total
bodies to HCV (Table 1). Control individuals were 4818 healthy blood donors and 385 pregnant women attending the hospital blood bank and antenatal clinic respectively. The 181 liver disease patients included 139 patients with chronic liver disease (CLD) and 42 patients with hepatocellular carcinoma (HCC). These patients were ‘seen at the Gastroenterology and Medical departments of the Riyadh Military Hospital, Saudi Arabia. The presence of chronic liver disease was defined both clinically and biochemically (raised serum aspartate transaminase level above 45 U/L for more than 6 months). All patients had relevant clinical
Correspondence: Dr S. Shariq, Armed Forces Hospital, PO Box 7897, Riyadh 1 1 159, Saudi Arabia. Accepted for publication 26 August 1991.
M . A . A1 Karawi et al.
238
Table 2 shows the prevalence of antibody to HCV in different aetiological subgroups of the C L D patients. The seropositivity for chronic hepatitis B patients was 13.9%, while it was 23.5% and 51.2% for schistosomal liver disease and non-A, non-B hepatitis respectively. A prevalence rate of 42.8% and 40% was noted for autoimmune liver disease and C L D of unknown aetiology. None of the alcoholic liver disease and haemochromatosis patients had antibodies to HCV. In Table 3, the HCV seropositivity among histologically verified cases was 27.3% for chronic persistent hepatitis, 27.8% for chronic active hepatitis, 28.6"/0 for cirrhosis and 26.2% for HCC. HBsAg was more prevalent in all groups: 36.4% for chronic persistent hepatitis, 44.4% for chronic active hepatitis, 39.3% for cirrhosis and 45.2% for HCC. Interestingly, the rates of absent markers in all these groups were very similar to anti-HCV prevalences.
details and underwent complete haematological and biochemical (including a-fetoprotein [AFP]) serological tests for HBV, HCV and schistosomiasis, as well as upper gastrointestinal endoscopy and abdominal ultrasound. Histological diagnosis was available in 57 of 139 C L D patients and in all HCC patients. Of 139 C L D patients (nearly all Saudis), 106 were males and 33 were females. Their mean age was 56.4 years (range 21-85 years). There were 38 males and 4 females among 42 patients with histologically proven HCC, and their mean age was 59.6 years (range 35-88 years). Serum specimens were collected and kept frozen at -20°C until tested. Antibodies to HCV were measured by commercially available enzyme immunoassay (Abbott Laboratories, Chicago, IL, USA), which detects antibody against a recombinant polypeptide C100-3.7 Only repeatedly reactive sera were considered as positive. HBsAg was assayed by using enzyme immunoassay (AUSZYME, Abbott Laboratories) and reactive sera were confirmed by neutralization tests according to manufacturer's instructions.
DISCUSSION Since the introduction of HCV antibody test, a great deal of information has accrued with regard to the frequency of HCV prevalence in various disease states. Most of the information has come from Western and little from Asian and African countries.14315 This report demonstrates the presence and significance of HCV in Saudi Arabia. T h e anti-HCV positive prevalence of 1.Sohamong healthy blood donors in the Saudi population is comparable to that reported from Japan," but slightly higher than in the USA and German~.'.'~ An anti-HCV prevalence of 37.5% and 42.3% was found in patients with HBsAg negative chronic liver disease and HCC respectively. This is lower than that in Italian," Spanish" and Taiwanese14 patients. A review of clinical notes showed that no more than one quarter of anti-HCV positive patients with C L D or HCC had received a blood transfusion 6-20 years before diagnosis. Although the main established mode of HCV transmission is parenteral, other mechanisms of transmission occur through an unidentified route. Evidence for sexual and perinatal transmission is scarce." The relationship of HCV with flaviviruses raises the possibility that HCV might also be transmitted by vectors, although epidemiologic trends d o not suggest such transmission.20 Although seropositivity for anti-HCV is currently inter-
RESULTS Table 1 shows the prevalence of antibody to HCV in various groups studied. Among the controls, the overall prevalence of anti-HCV was 1.5%. In patients with chronic liver disease, the anti-HCV prevalence was 13.9% in HBsAg positive cases and 37.5% in HBsAg negative cases, whereas in patients with HCC the prevalence was 12.5% in HBsAg positive cases and 42.3% in HBsAg negative cases. The prevalence in all the liver disease patients averaged 30.4% (55/18 1). Table 2 Prevalence of anti-HCV in chronic liver disease
Anti-HCV positive Aetiology
Chronic hepatitis B Non-A, non-B hepatitis Schistosomal liver disease Autoimmune liver disease Alcoholic liver disease Haemochromatosis Unknown Total
No. tested
n
YO
43 41 34 7 2 2 10
6 21 8 3 0 0 4
13.9 51.2 23.5 42.8 0 0 40
139
42
30.2
Table 3 Liver histology in relation to HCV and HBV markers
Anti-HCV Histological diagnosis Chronic persistent hepatitis Chronic active hepatitis Cirrhosis of liver Total (CLD) Hepatocellularcarcinoma
No. studied 11 18 28 57 42
n (Yo)
3 5 8 16
(27.3) (27.8) (28.6) (28.1) 11 (26.2)
HBsAg n
(Oh)
4 (36.4) 8 (44.4) 11 (39.3) 23 (40.4) 19 (45.2)
Anti-HCV and anti-HBsAg No. markers n (YO) n (YO) I 0 2 3 2
(9.1) (0) (7.1) (5.3) (4.8)
3 (27.3) 5 (27.8) 7 (25) 15 (26.3) 10 (23.8)
Hepatitis C infection in CLD and HCC
preted as evidence of HCV confirmation, further tests like recombinant immunoblot assay (RIBA) and polymerase chain reaction (PCR) seem necessary. Moreover, strong reactivity for this antibody does suggest active HCV replication.” Nevertheless this possibility must be confirmed by further tests. In patients with chronic hepatitis and HCC who were HBsAg positive, anti-HCV was present in 13.9%and 12.5%, respectively. This is in marked contrast to the 37.5-42.3% prevalence found in HBsAg negative patients, and further supports the same observation in patients with chronic liver disease. Lack of viral markers in the 99 patients with histologically confirmed diagnosis (Table 3) was almost identical to the anti-HCV prevalence rates in this group, and implies that in about 25% of Saudi patients other factors and/or aetiologies need to be sought. In Italy” and Spain,” the correlation of HCC with anti-HCV was more evident, but the most striking finding came from Japan, where 94.4% of patients with non-A, non-B post-transfusion hepatitis-related HCC had anti-HCV positivity; as well as indicating a high rate of progression to HCC with a mean interval of 30 years from the date of transfusion.21 In a US study, only 1821% of HCC patients had HBs antigenaemia,22 and in another report HBsAg negative patients with HCC had an anti-HCV prevalence of 53O/0,~~which is higher than the 42.3% in this study (Table 1). Although not proven by direct demonstration of viral RNA in tumour tissue, HCV appears to be an important aetiologic agent in the development of HCC. It is too early to ascertain whether this is the result of a direct oncogenic effect or merely the result of the malignant transformation of cells undergoing rapid regeneration.20 The data indicate that HCV infection has a relatively minor role in HBsAg positive chronic liver disease and hepatocellular carcinoma in Saudi Arabia, but that it is important in HBsAg negative individuals with these conditions.
REFERENCES 1. ARYAS. C. Viral hepatitis in Saudi Arabia: What next during the 1990s?Saudi Med. J. 1989; 10: 267-72. 0. A. The epidemiology of viral hepatitis in the 2. SHOBOKSHI western region of Saudi Arabia. Ann. Saudi Med. 1988; 8: 81(A). 3. KINGSTON M. E., ALI M. A., ATIYEHM. & DONNELLY R. J. Diagnosis of chronic active hepatitis: A review of 100 cases. King Faisal Special. Hosp. Med. 3.1984; 4: 9-16. 4. AL FALEH F. Z. Hepatitis B infection in Saudi Arabia. Ann. Saudi Med. 1988; 8: 474-80.
239
5 . SEBAI Z. A. Schistosomiasis in Saudi Arabia. Ann. Saudi Med. 1988; 8: 169-74. 6. C H OQ. ~ L., KUOG . , WEINER A. J . et al. Isolation of a DNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989; 244: 359-62. 7. KUO G., CHOOQ. L., ALTER H. J. et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989; 244: 362-4. 8. ALTER H. J., PURCELL R. H., SHIHJ. W. et al. Detection of antibody to hepatitis C virus in prospectivcly followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N. Engl. J . Med. 1989; 321: 1494-500. 9. KRAULEDAT P. B. Report of the Proceedings: First International Symposium on hepatitis C zincs. Rome, Italy, 1989. 10. COLOMBO M., Kuo G., CHOOQ. L. et al. Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma. Lancet 1989; ii: 1006-8. 11. ESTEBAN J . I., ESTEBAN R., VILADOMILI L. et al. Hepatitis C virus antibodies among risk groups in Spain. Lancet 1989; ii: 294-7. 12. VAN DER POEL c . L., REESINK H. w., LELIEP. N. et al. Antihepatitis C antibodies and non-A, non-B post-transfusion hepatitis in the Netherlands. Lancet 1989; ii: 297-8. 13. JACYNA M. R.,O’NEILK., BROWN J. et al. Hepatitis C virus antibodies in subjects with and without liver disease in the United Kingdom. Quart. J . Med. 1990; 282: 1009-12. 14. CHEND. S., KUOG. C., SUNGJ. L. et al. Hepatitis C virus infection in an area hyperendemic for hepatitis B and chronic liver disease: The Taiwan experience. 3.In5 Dis. 1990; 161: 817-22. 15. KEWM. C., HOUGHTON M., CHOOQ . L., KUOG. Hepatitis C virus antibodies in southern African blacks with hepatocellular carcinoma. Lancet 1990; 335: 873-4. 16. KAMITSUSKASA H., HARADA H., YAKURAM. et al. Intrafamilial transmission of hepatitis C virus. Lancet 1989; 2: 987. 17. KUHNL P., SIEDLS., STANGEL W. et al. Antibody to hepatitis C virus in German blood donors. Lancer 1989; ii: 324. 18. ALTERM. J. & SAMPLINER R. E. Hepatitis C: And miles to go before we sleep. N. Engl. J . Med. 1989; 321: 1538-40. 19. ALTER M. J . , GERETYJ. & SMALLWOOD L. A. Sporadic nonA, non-B hepatitis: Frequency and epidemiology in an urban US population. 3.Infect. Dis. 1982; 145: 886-93. 20. ALTER H. J. The hepatitis C virus and its relationship to the clinical spectrum of NANB hepatitis.J . Gasiroenterol. Heparol. 1990 (Suppl. 1); 78-94. 21. KIYOSAWA K., SODEYAMA T., TANARA 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. 22. AUSTINH., SELZELLA E., GRUFFERMAN S. et al. A case control study of hepatocellular carcinoma and hepatitis B virus, cigarette smoking and alcohol consumption. Cancer Res. 1985; 46: 962-6. 23. HASANF., LENNOXJ. et al. Hepatitis C-associated hepatocellularcarcinoma. Hepatology 1990; 12: 589-91.
LIVER AND BILIARY Hepatitis C virus infection in chronic liver disease and hepatocellular carcinoma in Saudi Arabia MOHAMED ALI AL KARAWI,* SOHAIL SHARIQ,* ABDEL RAHMAN EL SHIEKH MOHAMED,* AWAD A. SAEEDt AND ABDUL MUTAAL MOHAMED AHMED. *Gastroenterology Division and tMicrobiology Division, Armed Forces Hospital, Riyadh, Saudi Arabia Abstract The prevalence of antibody to hepatitis C virus (HCV) was determined in 139 patients with chronic liver disease (CLD) and 42 patients with hepatocellular carcinoma (HCC) during one year at the Riyadh Military Hospital, Saudi Arabia. The anti-HCV was detected in 36 of 96 (37.5%) HBsAg-negative patients with chronic liver disease and six of 43 (13.9%) HBsAg-positive patients with chronic liver disease. In addition, 1 1 (42.3%)HBsAg-negative hepatocellular carcinoma patients and two of 16 (12.5°/~)HBsAg-positive hepatocellular patients had antibody to HCV. The anti-HCV prevalence was 1.5% in 4818 healthy blood donors and 1% in 385 antenatal patients. The overall HCV seropositivity of 30.4% in 181 liver disease patients (CLD and HCC) in Saudi Arabia is lower than that reported from European countries.
Key words: chronic liver disease, hepatitis C, hepatocellular carcinoma.
INTRODUCTION Non-alcoholic chronic liver disease is a frequent cause of significant morbidity and mortality in Saudi Arabia. Besides known microbial agents like hepatitis B virus4 and Schistosomu mansoni causing chronic liver disease in the Arab penninsula,’ it had been apparent for a number of years that another agent was responsible for a significant number of acute and chronic hepatitis. It remained elusive despite intensive effort for over a decade until a major breakthrough came when a portion of the genome of a non-A, non-B hepatitis virus designated as hepatitis C virus (HCV) was cloned in 1989,6 and a specific immunoassay for HCV antibodies (anti-HCV) was developed.’ Subsequently, antiHCV was reported in a high proportion of patients with post-transfusion chronic non-A, non-B hepatitis,* and more frequently in the general community in the absence of any prior history of transfusion.’ This article describes the prevalence of HCV infection in Saudi Arabia and its relation to chronic liver disease and hepatocellular carcinoma. For comparison with the normal population, the prevalence was studied in apparently healthy blood donors and antenatal women.
METHODS During one year (October 1989-October 1990), blood samples from 5384 patients and subjects were studied for anti-
Table 1 Prevalence of antibody to hepatitis C virus in different population groups
Subjects
No. studied
Anti-HCV n ‘YO
Volunteer blood donor Antenatal
4818 385
72 4
1.5 1
Total
5203
76
1.5
43 96
6 36
13.9 37.5
16 26
2 11
12.5 42.3
181
55
30.4
Chronic liver disease (n = 139) HBsAg positive HBsAg negative Hepatocellular carcinoma (n = 42) HBsAg positive HBsAg negative Total
bodies to HCV (Table 1). Control individuals were 4818 healthy blood donors and 385 pregnant women attending the hospital blood bank and antenatal clinic respectively. The 181 liver disease patients included 139 patients with chronic liver disease (CLD) and 42 patients with hepatocellular carcinoma (HCC). These patients were ‘seen at the Gastroenterology and Medical departments of the Riyadh Military Hospital, Saudi Arabia. The presence of chronic liver disease was defined both clinically and biochemically (raised serum aspartate transaminase level above 45 U/L for more than 6 months). All patients had relevant clinical
Correspondence: Dr S. Shariq, Armed Forces Hospital, PO Box 7897, Riyadh 1 1 159, Saudi Arabia. Accepted for publication 26 August 1991.
M . A . A1 Karawi et al.
238
Table 2 shows the prevalence of antibody to HCV in different aetiological subgroups of the C L D patients. The seropositivity for chronic hepatitis B patients was 13.9%, while it was 23.5% and 51.2% for schistosomal liver disease and non-A, non-B hepatitis respectively. A prevalence rate of 42.8% and 40% was noted for autoimmune liver disease and C L D of unknown aetiology. None of the alcoholic liver disease and haemochromatosis patients had antibodies to HCV. In Table 3, the HCV seropositivity among histologically verified cases was 27.3% for chronic persistent hepatitis, 27.8% for chronic active hepatitis, 28.6"/0 for cirrhosis and 26.2% for HCC. HBsAg was more prevalent in all groups: 36.4% for chronic persistent hepatitis, 44.4% for chronic active hepatitis, 39.3% for cirrhosis and 45.2% for HCC. Interestingly, the rates of absent markers in all these groups were very similar to anti-HCV prevalences.
details and underwent complete haematological and biochemical (including a-fetoprotein [AFP]) serological tests for HBV, HCV and schistosomiasis, as well as upper gastrointestinal endoscopy and abdominal ultrasound. Histological diagnosis was available in 57 of 139 C L D patients and in all HCC patients. Of 139 C L D patients (nearly all Saudis), 106 were males and 33 were females. Their mean age was 56.4 years (range 21-85 years). There were 38 males and 4 females among 42 patients with histologically proven HCC, and their mean age was 59.6 years (range 35-88 years). Serum specimens were collected and kept frozen at -20°C until tested. Antibodies to HCV were measured by commercially available enzyme immunoassay (Abbott Laboratories, Chicago, IL, USA), which detects antibody against a recombinant polypeptide C100-3.7 Only repeatedly reactive sera were considered as positive. HBsAg was assayed by using enzyme immunoassay (AUSZYME, Abbott Laboratories) and reactive sera were confirmed by neutralization tests according to manufacturer's instructions.
DISCUSSION Since the introduction of HCV antibody test, a great deal of information has accrued with regard to the frequency of HCV prevalence in various disease states. Most of the information has come from Western and little from Asian and African countries.14315 This report demonstrates the presence and significance of HCV in Saudi Arabia. T h e anti-HCV positive prevalence of 1.Sohamong healthy blood donors in the Saudi population is comparable to that reported from Japan," but slightly higher than in the USA and German~.'.'~ An anti-HCV prevalence of 37.5% and 42.3% was found in patients with HBsAg negative chronic liver disease and HCC respectively. This is lower than that in Italian," Spanish" and Taiwanese14 patients. A review of clinical notes showed that no more than one quarter of anti-HCV positive patients with C L D or HCC had received a blood transfusion 6-20 years before diagnosis. Although the main established mode of HCV transmission is parenteral, other mechanisms of transmission occur through an unidentified route. Evidence for sexual and perinatal transmission is scarce." The relationship of HCV with flaviviruses raises the possibility that HCV might also be transmitted by vectors, although epidemiologic trends d o not suggest such transmission.20 Although seropositivity for anti-HCV is currently inter-
RESULTS Table 1 shows the prevalence of antibody to HCV in various groups studied. Among the controls, the overall prevalence of anti-HCV was 1.5%. In patients with chronic liver disease, the anti-HCV prevalence was 13.9% in HBsAg positive cases and 37.5% in HBsAg negative cases, whereas in patients with HCC the prevalence was 12.5% in HBsAg positive cases and 42.3% in HBsAg negative cases. The prevalence in all the liver disease patients averaged 30.4% (55/18 1). Table 2 Prevalence of anti-HCV in chronic liver disease
Anti-HCV positive Aetiology
Chronic hepatitis B Non-A, non-B hepatitis Schistosomal liver disease Autoimmune liver disease Alcoholic liver disease Haemochromatosis Unknown Total
No. tested
n
YO
43 41 34 7 2 2 10
6 21 8 3 0 0 4
13.9 51.2 23.5 42.8 0 0 40
139
42
30.2
Table 3 Liver histology in relation to HCV and HBV markers
Anti-HCV Histological diagnosis Chronic persistent hepatitis Chronic active hepatitis Cirrhosis of liver Total (CLD) Hepatocellularcarcinoma
No. studied 11 18 28 57 42
n (Yo)
3 5 8 16
(27.3) (27.8) (28.6) (28.1) 11 (26.2)
HBsAg n
(Oh)
4 (36.4) 8 (44.4) 11 (39.3) 23 (40.4) 19 (45.2)
Anti-HCV and anti-HBsAg No. markers n (YO) n (YO) I 0 2 3 2
(9.1) (0) (7.1) (5.3) (4.8)
3 (27.3) 5 (27.8) 7 (25) 15 (26.3) 10 (23.8)
Hepatitis C infection in CLD and HCC
preted as evidence of HCV confirmation, further tests like recombinant immunoblot assay (RIBA) and polymerase chain reaction (PCR) seem necessary. Moreover, strong reactivity for this antibody does suggest active HCV replication.” Nevertheless this possibility must be confirmed by further tests. In patients with chronic hepatitis and HCC who were HBsAg positive, anti-HCV was present in 13.9%and 12.5%, respectively. This is in marked contrast to the 37.5-42.3% prevalence found in HBsAg negative patients, and further supports the same observation in patients with chronic liver disease. Lack of viral markers in the 99 patients with histologically confirmed diagnosis (Table 3) was almost identical to the anti-HCV prevalence rates in this group, and implies that in about 25% of Saudi patients other factors and/or aetiologies need to be sought. In Italy” and Spain,” the correlation of HCC with anti-HCV was more evident, but the most striking finding came from Japan, where 94.4% of patients with non-A, non-B post-transfusion hepatitis-related HCC had anti-HCV positivity; as well as indicating a high rate of progression to HCC with a mean interval of 30 years from the date of transfusion.21 In a US study, only 1821% of HCC patients had HBs antigenaemia,22 and in another report HBsAg negative patients with HCC had an anti-HCV prevalence of 53O/0,~~which is higher than the 42.3% in this study (Table 1). Although not proven by direct demonstration of viral RNA in tumour tissue, HCV appears to be an important aetiologic agent in the development of HCC. It is too early to ascertain whether this is the result of a direct oncogenic effect or merely the result of the malignant transformation of cells undergoing rapid regeneration.20 The data indicate that HCV infection has a relatively minor role in HBsAg positive chronic liver disease and hepatocellular carcinoma in Saudi Arabia, but that it is important in HBsAg negative individuals with these conditions.
REFERENCES 1. ARYAS. C. Viral hepatitis in Saudi Arabia: What next during the 1990s?Saudi Med. J. 1989; 10: 267-72. 0. A. The epidemiology of viral hepatitis in the 2. SHOBOKSHI western region of Saudi Arabia. Ann. Saudi Med. 1988; 8: 81(A). 3. KINGSTON M. E., ALI M. A., ATIYEHM. & DONNELLY R. J. Diagnosis of chronic active hepatitis: A review of 100 cases. King Faisal Special. Hosp. Med. 3.1984; 4: 9-16. 4. AL FALEH F. Z. Hepatitis B infection in Saudi Arabia. Ann. Saudi Med. 1988; 8: 474-80.
239
5 . SEBAI Z. A. Schistosomiasis in Saudi Arabia. Ann. Saudi Med. 1988; 8: 169-74. 6. C H OQ. ~ L., KUOG . , WEINER A. J . et al. Isolation of a DNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989; 244: 359-62. 7. KUO G., CHOOQ. L., ALTER H. J. et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989; 244: 362-4. 8. ALTER H. J., PURCELL R. H., SHIHJ. W. et al. Detection of antibody to hepatitis C virus in prospectivcly followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N. Engl. J . Med. 1989; 321: 1494-500. 9. KRAULEDAT P. B. Report of the Proceedings: First International Symposium on hepatitis C zincs. Rome, Italy, 1989. 10. COLOMBO M., Kuo G., CHOOQ. L. et al. Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma. Lancet 1989; ii: 1006-8. 11. ESTEBAN J . I., ESTEBAN R., VILADOMILI L. et al. Hepatitis C virus antibodies among risk groups in Spain. Lancet 1989; ii: 294-7. 12. VAN DER POEL c . L., REESINK H. w., LELIEP. N. et al. Antihepatitis C antibodies and non-A, non-B post-transfusion hepatitis in the Netherlands. Lancet 1989; ii: 297-8. 13. JACYNA M. R.,O’NEILK., BROWN J. et al. Hepatitis C virus antibodies in subjects with and without liver disease in the United Kingdom. Quart. J . Med. 1990; 282: 1009-12. 14. CHEND. S., KUOG. C., SUNGJ. L. et al. Hepatitis C virus infection in an area hyperendemic for hepatitis B and chronic liver disease: The Taiwan experience. 3.In5 Dis. 1990; 161: 817-22. 15. KEWM. C., HOUGHTON M., CHOOQ . L., KUOG. Hepatitis C virus antibodies in southern African blacks with hepatocellular carcinoma. Lancet 1990; 335: 873-4. 16. KAMITSUSKASA H., HARADA H., YAKURAM. et al. Intrafamilial transmission of hepatitis C virus. Lancet 1989; 2: 987. 17. KUHNL P., SIEDLS., STANGEL W. et al. Antibody to hepatitis C virus in German blood donors. Lancer 1989; ii: 324. 18. ALTERM. J. & SAMPLINER R. E. Hepatitis C: And miles to go before we sleep. N. Engl. J . Med. 1989; 321: 1538-40. 19. ALTER M. J . , GERETYJ. & SMALLWOOD L. A. Sporadic nonA, non-B hepatitis: Frequency and epidemiology in an urban US population. 3.Infect. Dis. 1982; 145: 886-93. 20. ALTER H. J. The hepatitis C virus and its relationship to the clinical spectrum of NANB hepatitis.J . Gasiroenterol. Heparol. 1990 (Suppl. 1); 78-94. 21. KIYOSAWA K., SODEYAMA T., TANARA 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. 22. AUSTINH., SELZELLA E., GRUFFERMAN S. et al. A case control study of hepatocellular carcinoma and hepatitis B virus, cigarette smoking and alcohol consumption. Cancer Res. 1985; 46: 962-6. 23. HASANF., LENNOXJ. et al. Hepatitis C-associated hepatocellularcarcinoma. Hepatology 1990; 12: 589-91.
