- Email: [email protected]
SEN virus infection in high- and non-endemic areas for hepatitis C in Japan
I-IEPATOLOGYVot. 34, No. 4, Pt. 2, 2001
AASLD ABSTRACTS
487A
1259
1260
LEVEL OF REPLICATION AND GENOTYPES OF HEPATITIS A VIRUS IN FULMINANT AND NON-FULMINANT HEPATITIS. Guillerme Rezende, Anne-Marie Roque, Michelle Gigou, Elisabeth Dussaix, David Challine, Didier Samuel, Cyrflle Feray, Paul Brousse Hospital, villejuif France
THROMBOTIC FACTORS AND EXTENT OF LIVER FIBROSIS IN CHRONIC VIRAL HEPATITIS. George V Papatheodoridis, Evmorfia Papakonstantinou, Acad Dept of Medicine, Hippokration Gen Hosp, Athens Greece; Evangelia Andrioti, 1st R Transfusion-Haemophilia Ctr, Hippokration Hosp, Athens Greece; Evangelos Cholongitas, Acad Dept of Medicine, Hippokration Gen Hosp, Athens Greece; Kalliopi Petraki, Pathology D e p t , Hippokration General Hospital, Athens Greece; Irene Kontopoulou, 1st R Transfusion-Haemophilia Ctr, Hippokration Hosp, Athens Greece; Stephanos J Hadziyannis, Acad Dept of Medicine, Hippokration Gen Hosp, Athens Greece
Fulminant hepatitis due to hepatitis A is an unfrequent disease. Very few data are: available on the level of replication of HAV and its possible relation wih the severity of liver disease. Cofactors such as drug toxicity are frequent in this setting. Patients and Methods: Among the 80 patients admitted for acute hepatitis A at our institution from 1984 until 2000, unthawed sera sampled at the admission and preserved in good conditions were available for 50 anti-HAV class IgM + patients (31 men, mean age 33 (16-63)). None had additional liver disease or coinfection by HIV or HBV. 26 had severe hepatitis with factor V < 50 % and 19 had fulminant hepatitis with encephalopathy and factor V < 30%. 10 were transplanted. Others had an usual course. Serum HAV RNA was amplified in VP1 regions by nested PCR to assess the viral genotype and quantified by TaqMan® real-time PCR. Results. Detection of HAV RNA by real-time PCR was possible in 39/50 sera. Genotypes were determined in 36 patients. Fulminant hepatitis was correlated to acetaminophen intake (p=0.05), female gender (p=0.01), other genotypes than l a (p=0.005) and low viremia (2 log -+ 1.8 vs 4.2 log -+ 1.6; p =0.001)). In multivariate analysis, female gender and low viremia were independent variables (p=0.01 and 0.004) . Similar findings were evidenced when the independent variable was the level of factor V at the admission. Time between the onset of icterus and admission were shorter in patients with severe disease and was not related to the level of viremia. Conclusion. Severe hepatitis A is strongly related to a low lewfl of replication as observed for Hepatitis B in similar setting. Direct pathogenicity of HAV is unlikely in the development of severe lesions during hepatit/s A. Level of replication could help to define patients with poor prognosis.
Thrombosis of small-sized intrahepatic veins has been suggested as a potential factor that might trigger liver tissue remodeling and protein C deficiency and/or elevated factor VIII levelshave been reported to be associated with extensive liver fibrosis in chronic hepatitis (CH)-C. We evaluated the levels or presence of multiple thrombotic factors and their association with the extent of fibrosis in 65 consecutive patients (47 males/18 females, mean age:45+ 14 years) with histologically documented CH-C (n=36) or CH-B (n=29, all HBeAg-/anti-HBe+). Patients with malignancy, history of venous thrombosis, or any type of antiviral or immunosuppressive therapy within the last 6 months were excluded. Liver biopsies were blindly evaluated according to the scoring system proposed by lshak et al (J Hepatol 1995- grading:0-18, staging:0-6). LFTs (ALT, AST, bilirubin, GGT, albumin, globulins), FBC including platelet count (PLT), PTfINR, APTT, fibrinogen levels, FS monomers, D-Dimers, presence of factor V Leiden (APC), mutation of prothrombin gene (PFII-20210A), presence of lupus anticoagulants, presence of anticardiolipin antibodies, and levels of antithrombin III (ATIII), protein C, protein S, factors VIII, IX, XI, XII, and plasminogen were determined in all patients on the liver biopsy date. Higher staging as a continuous variable was significantly associated with older age (P=0.001), higher grading (P<0.001), lower PLT (P=0.015), more prolonged PT/INR (P=0.008), lower ATIII levels (P<0.001), lower protein C levels (P<0.001), higher factor VIII levels (P=0.03) and lower plasminogen levels (P=0.001). Multiple regression analysis showed that lower ATIII or protein C levels were significantly associated with more extensive fibrosis independently of age and grading. Patients with staging 4-6 compared to those with staging 0-3 had significantly older age (53±16 vs 43+-14, P=0.02), higher grading (9.2+-2.3 vs 6.9+-2.2, P=0.002), lower ATIII levels (92-+ 19 vs 106-+ 13, P=0.009) or more frequently decreased (<80%) ATIII levels (5/17 or 29% vs 2/48 or 4%, P=0.01), lower protein C levels (78--21 vs 101+-21, P=0.001) or more frequently decreased (<70%) protein C levels (5/17 or 29% vs 2/48 or 4%, P=0.01), higher factor VIII levels (201---72 vs 152-+55, P=0.02) or relativelymore frequentlyincreased (>150%) factor VIII levels (12/17 or 71% vs 21/48 or 44%, P=0.10), and lower plasminogen levels (86-+t2 vs 96-+14, P=0.01) or relatively more frequently decreased (<75%) plasminogen levels (3/17 or 18% vs 1/48 or 2%, P= 0.052). In particular, decreased ATIII and/or protein C levels were detected in 9/17 (53%) patients with staging 4-6 and in only 3/45 (7%) patients with staging 0-3 (OR: 14.5, P<0.001). Logistic regression analysis showed that decreased levels of ATIII and/or protein C was the strongest factor associated with advanced (4-6) staging of CH (adjusted OR: 2.8, 95% C!: 1.2-6.6, P=0.01) regardless of age, grading, factor VIII or plasminogen levels. Conclusions: Decreased ATlll and/or protein C levels appear to be associated with more extensive fibrosis in patients with CH-C or B. Whether the association of such potentiallyprethrombotic conditions with more advanced staging of CH is a primary or secondary phenomenon and whether the development of such conditions in combination with local inflammation accelerate the progression of liver fibrosis should be evaluated in properly designed prospective studies.
1261
1262
W I D E DISTRIBUTION OF T I V DNA IN DIFFERENT BODY FLUIDS INCLUDING INFANT CORD BLOOD; POSSIBILITY OF MOTHER TO-NEONATAL TRANSMISSION. Hiroshi Matsubara, Kojiro Michitaka, Norio Horiike, Morikazu Onji, Ehime University School of Medicine, Shigenobu Japan
SEN VIRUS INFECTION IN HIGH- AND NON-ENDEMIC AREAS FOR HEPATITIS C IN JAPAN. Takeji Umemura, Harvey J Alter, NIH, Bethesda, MD; Eiji Tanaka, Shinshu University School of Medicine, Matsumoto Japan; Anthony E Yeo,James W Shih, NIH, Bethesda, MD; Koji Orii, Akihiro Matsumoto, Kaname Yoshizawa, Kendo Kiyosawa, Shinshu University School of Medicine, Matsumoto Japan
Background/Aims: Although TT virus (TTV) DNA is readily detected in the serum from a considerable numbers of general population, further study about the route of transmission of this virus is warranted. To have insights in this regard, we checked TTV DNA in different body fluids from serum TTV DNApositive persons. Furthermore, we also checked the existence of TTV DNA in different body fluids of the pregnant mothers and their new born infants to evaluate the role of neonatal transmission in this regard. Subjects and methods: The experiments were conducted in two phases. First, TTV DNA was checked in the different body fluids (saliva, stool, semen, tear, urine and sweat) from 11 serum TTV DNA-positive volunteers. In the next step, a total of 52 pregnant women with normal serum alanine aminotransferase levels and all of their new born babies were enrolled in the study to check TTV DNA. Sera were taken front the mothers prior to delivery, whereas, the amniotic fluid were collected during deliver. Breast milk was usually taken from the mothers within one week of delivery. Cord blood was collected from the new born infants just after birth. Peripheral blood was taken from these infants usually within 1-3 days after birth. Total DNA was isolated from different samples and the existence of TTV DNA was confirmed by a polymerase chain reaction using broad-based TTV DNA-specific primers. Results: TTV DNA was detected in the saliva, stool, semen and tears from all serum TTV DNA-positive volunteers. Regarding the pregnant mothers, TTV DNA was detected in 40/52 (77%) of the mothers sera. TTV DNA was also detected in the cord blood from 25/52 (48%) of the new born infants. TTV DNA was also seen in the breast milk from 35/52 (67%), in the amniotic fluid from 6/6 (100%) pregnant mothers, and in the sera from 8 of 11 ('?3%) new born infants. Conclusions: Our data suggest a widespread distribution of TTV DNA in different body fluids in serum TTV DNA-positive subjects. Data from the pregnant mother and their new born infants indicate that intrauterine transmission or transmission via breast milk may contribute to maintain the global TTV reservoir.
Objectives: SEN virus (SEN-V) is a recently identified single-stranded circular DNA virus. A strong association between two SEN-V variants, designated SENV-D and SENV-H and transfusion-associated non-A to E hepatitis has been reported. In this study, the prevalence, transmission routes, and clinical significance of SENV-D and SENV-H infections in high- and non-endemic areas for hepatitis C virus (HCV) infection in Japan are described. Patients and Methods: Two hundred individuals from a highly HCV endemic area (30% anti-HCV positive) and 194 individuals from a HCV non-endemic area (1% anti-HCV positive) were selected randomly for analysis from a medical screening survey for liver disease in 1993. SENV-D DNA and SENV-H DNA in serum were detected by polymerase chain reaction using strain-specific primers. Resuits: SEN-V DNA was detected in 112 of 200 (56%) subjects in the HCV high-endemic area, and 118 (61%) subjects in the HCV non-endemic area. Age specific prevalence of SEN-V DNA was similar to that of TTV DNA being equally distributed at all ages in both areas, but differed from that of HCV which predominated in the elderly suggesting a cohort effect. As opposed to HCV, SEN-V infection was not associated with surgical procedures, blood transfusion or folk medicine practice. TTV infection was significantly more prevalent in SEN-V DNA positive subjects than in SEN-V DNA negative subjects in both areas (high-endemic area: 67% vs. 44% p=0.002, non-endemic area: 52% vs. 30% p=0.005). In contrast, HCV prevalence did not correlate with SEN-V status in either region. Serum ALT level was significantly associated with HCV viremia, but not SEN-V viremia (p<0.001). Conclusions: SEN-V infection was common in areas of both high and low HCV prevalence in Japan. SEN-V appears to have transmission routes and age-related prevalence distinct from HCV. There was no apparent association between SEN-V viremia and biochemical evidence of hepatitis.
AASLD ABSTRACTS
487A
1259
1260
LEVEL OF REPLICATION AND GENOTYPES OF HEPATITIS A VIRUS IN FULMINANT AND NON-FULMINANT HEPATITIS. Guillerme Rezende, Anne-Marie Roque, Michelle Gigou, Elisabeth Dussaix, David Challine, Didier Samuel, Cyrflle Feray, Paul Brousse Hospital, villejuif France
THROMBOTIC FACTORS AND EXTENT OF LIVER FIBROSIS IN CHRONIC VIRAL HEPATITIS. George V Papatheodoridis, Evmorfia Papakonstantinou, Acad Dept of Medicine, Hippokration Gen Hosp, Athens Greece; Evangelia Andrioti, 1st R Transfusion-Haemophilia Ctr, Hippokration Hosp, Athens Greece; Evangelos Cholongitas, Acad Dept of Medicine, Hippokration Gen Hosp, Athens Greece; Kalliopi Petraki, Pathology D e p t , Hippokration General Hospital, Athens Greece; Irene Kontopoulou, 1st R Transfusion-Haemophilia Ctr, Hippokration Hosp, Athens Greece; Stephanos J Hadziyannis, Acad Dept of Medicine, Hippokration Gen Hosp, Athens Greece
Fulminant hepatitis due to hepatitis A is an unfrequent disease. Very few data are: available on the level of replication of HAV and its possible relation wih the severity of liver disease. Cofactors such as drug toxicity are frequent in this setting. Patients and Methods: Among the 80 patients admitted for acute hepatitis A at our institution from 1984 until 2000, unthawed sera sampled at the admission and preserved in good conditions were available for 50 anti-HAV class IgM + patients (31 men, mean age 33 (16-63)). None had additional liver disease or coinfection by HIV or HBV. 26 had severe hepatitis with factor V < 50 % and 19 had fulminant hepatitis with encephalopathy and factor V < 30%. 10 were transplanted. Others had an usual course. Serum HAV RNA was amplified in VP1 regions by nested PCR to assess the viral genotype and quantified by TaqMan® real-time PCR. Results. Detection of HAV RNA by real-time PCR was possible in 39/50 sera. Genotypes were determined in 36 patients. Fulminant hepatitis was correlated to acetaminophen intake (p=0.05), female gender (p=0.01), other genotypes than l a (p=0.005) and low viremia (2 log -+ 1.8 vs 4.2 log -+ 1.6; p =0.001)). In multivariate analysis, female gender and low viremia were independent variables (p=0.01 and 0.004) . Similar findings were evidenced when the independent variable was the level of factor V at the admission. Time between the onset of icterus and admission were shorter in patients with severe disease and was not related to the level of viremia. Conclusion. Severe hepatitis A is strongly related to a low lewfl of replication as observed for Hepatitis B in similar setting. Direct pathogenicity of HAV is unlikely in the development of severe lesions during hepatit/s A. Level of replication could help to define patients with poor prognosis.
Thrombosis of small-sized intrahepatic veins has been suggested as a potential factor that might trigger liver tissue remodeling and protein C deficiency and/or elevated factor VIII levelshave been reported to be associated with extensive liver fibrosis in chronic hepatitis (CH)-C. We evaluated the levels or presence of multiple thrombotic factors and their association with the extent of fibrosis in 65 consecutive patients (47 males/18 females, mean age:45+ 14 years) with histologically documented CH-C (n=36) or CH-B (n=29, all HBeAg-/anti-HBe+). Patients with malignancy, history of venous thrombosis, or any type of antiviral or immunosuppressive therapy within the last 6 months were excluded. Liver biopsies were blindly evaluated according to the scoring system proposed by lshak et al (J Hepatol 1995- grading:0-18, staging:0-6). LFTs (ALT, AST, bilirubin, GGT, albumin, globulins), FBC including platelet count (PLT), PTfINR, APTT, fibrinogen levels, FS monomers, D-Dimers, presence of factor V Leiden (APC), mutation of prothrombin gene (PFII-20210A), presence of lupus anticoagulants, presence of anticardiolipin antibodies, and levels of antithrombin III (ATIII), protein C, protein S, factors VIII, IX, XI, XII, and plasminogen were determined in all patients on the liver biopsy date. Higher staging as a continuous variable was significantly associated with older age (P=0.001), higher grading (P<0.001), lower PLT (P=0.015), more prolonged PT/INR (P=0.008), lower ATIII levels (P<0.001), lower protein C levels (P<0.001), higher factor VIII levels (P=0.03) and lower plasminogen levels (P=0.001). Multiple regression analysis showed that lower ATIII or protein C levels were significantly associated with more extensive fibrosis independently of age and grading. Patients with staging 4-6 compared to those with staging 0-3 had significantly older age (53±16 vs 43+-14, P=0.02), higher grading (9.2+-2.3 vs 6.9+-2.2, P=0.002), lower ATIII levels (92-+ 19 vs 106-+ 13, P=0.009) or more frequently decreased (<80%) ATIII levels (5/17 or 29% vs 2/48 or 4%, P=0.01), lower protein C levels (78--21 vs 101+-21, P=0.001) or more frequently decreased (<70%) protein C levels (5/17 or 29% vs 2/48 or 4%, P=0.01), higher factor VIII levels (201---72 vs 152-+55, P=0.02) or relativelymore frequentlyincreased (>150%) factor VIII levels (12/17 or 71% vs 21/48 or 44%, P=0.10), and lower plasminogen levels (86-+t2 vs 96-+14, P=0.01) or relatively more frequently decreased (<75%) plasminogen levels (3/17 or 18% vs 1/48 or 2%, P= 0.052). In particular, decreased ATIII and/or protein C levels were detected in 9/17 (53%) patients with staging 4-6 and in only 3/45 (7%) patients with staging 0-3 (OR: 14.5, P<0.001). Logistic regression analysis showed that decreased levels of ATIII and/or protein C was the strongest factor associated with advanced (4-6) staging of CH (adjusted OR: 2.8, 95% C!: 1.2-6.6, P=0.01) regardless of age, grading, factor VIII or plasminogen levels. Conclusions: Decreased ATlll and/or protein C levels appear to be associated with more extensive fibrosis in patients with CH-C or B. Whether the association of such potentiallyprethrombotic conditions with more advanced staging of CH is a primary or secondary phenomenon and whether the development of such conditions in combination with local inflammation accelerate the progression of liver fibrosis should be evaluated in properly designed prospective studies.
1261
1262
W I D E DISTRIBUTION OF T I V DNA IN DIFFERENT BODY FLUIDS INCLUDING INFANT CORD BLOOD; POSSIBILITY OF MOTHER TO-NEONATAL TRANSMISSION. Hiroshi Matsubara, Kojiro Michitaka, Norio Horiike, Morikazu Onji, Ehime University School of Medicine, Shigenobu Japan
SEN VIRUS INFECTION IN HIGH- AND NON-ENDEMIC AREAS FOR HEPATITIS C IN JAPAN. Takeji Umemura, Harvey J Alter, NIH, Bethesda, MD; Eiji Tanaka, Shinshu University School of Medicine, Matsumoto Japan; Anthony E Yeo,James W Shih, NIH, Bethesda, MD; Koji Orii, Akihiro Matsumoto, Kaname Yoshizawa, Kendo Kiyosawa, Shinshu University School of Medicine, Matsumoto Japan
Background/Aims: Although TT virus (TTV) DNA is readily detected in the serum from a considerable numbers of general population, further study about the route of transmission of this virus is warranted. To have insights in this regard, we checked TTV DNA in different body fluids from serum TTV DNApositive persons. Furthermore, we also checked the existence of TTV DNA in different body fluids of the pregnant mothers and their new born infants to evaluate the role of neonatal transmission in this regard. Subjects and methods: The experiments were conducted in two phases. First, TTV DNA was checked in the different body fluids (saliva, stool, semen, tear, urine and sweat) from 11 serum TTV DNA-positive volunteers. In the next step, a total of 52 pregnant women with normal serum alanine aminotransferase levels and all of their new born babies were enrolled in the study to check TTV DNA. Sera were taken front the mothers prior to delivery, whereas, the amniotic fluid were collected during deliver. Breast milk was usually taken from the mothers within one week of delivery. Cord blood was collected from the new born infants just after birth. Peripheral blood was taken from these infants usually within 1-3 days after birth. Total DNA was isolated from different samples and the existence of TTV DNA was confirmed by a polymerase chain reaction using broad-based TTV DNA-specific primers. Results: TTV DNA was detected in the saliva, stool, semen and tears from all serum TTV DNA-positive volunteers. Regarding the pregnant mothers, TTV DNA was detected in 40/52 (77%) of the mothers sera. TTV DNA was also detected in the cord blood from 25/52 (48%) of the new born infants. TTV DNA was also seen in the breast milk from 35/52 (67%), in the amniotic fluid from 6/6 (100%) pregnant mothers, and in the sera from 8 of 11 ('?3%) new born infants. Conclusions: Our data suggest a widespread distribution of TTV DNA in different body fluids in serum TTV DNA-positive subjects. Data from the pregnant mother and their new born infants indicate that intrauterine transmission or transmission via breast milk may contribute to maintain the global TTV reservoir.
Objectives: SEN virus (SEN-V) is a recently identified single-stranded circular DNA virus. A strong association between two SEN-V variants, designated SENV-D and SENV-H and transfusion-associated non-A to E hepatitis has been reported. In this study, the prevalence, transmission routes, and clinical significance of SENV-D and SENV-H infections in high- and non-endemic areas for hepatitis C virus (HCV) infection in Japan are described. Patients and Methods: Two hundred individuals from a highly HCV endemic area (30% anti-HCV positive) and 194 individuals from a HCV non-endemic area (1% anti-HCV positive) were selected randomly for analysis from a medical screening survey for liver disease in 1993. SENV-D DNA and SENV-H DNA in serum were detected by polymerase chain reaction using strain-specific primers. Resuits: SEN-V DNA was detected in 112 of 200 (56%) subjects in the HCV high-endemic area, and 118 (61%) subjects in the HCV non-endemic area. Age specific prevalence of SEN-V DNA was similar to that of TTV DNA being equally distributed at all ages in both areas, but differed from that of HCV which predominated in the elderly suggesting a cohort effect. As opposed to HCV, SEN-V infection was not associated with surgical procedures, blood transfusion or folk medicine practice. TTV infection was significantly more prevalent in SEN-V DNA positive subjects than in SEN-V DNA negative subjects in both areas (high-endemic area: 67% vs. 44% p=0.002, non-endemic area: 52% vs. 30% p=0.005). In contrast, HCV prevalence did not correlate with SEN-V status in either region. Serum ALT level was significantly associated with HCV viremia, but not SEN-V viremia (p<0.001). Conclusions: SEN-V infection was common in areas of both high and low HCV prevalence in Japan. SEN-V appears to have transmission routes and age-related prevalence distinct from HCV. There was no apparent association between SEN-V viremia and biochemical evidence of hepatitis.