Tropical gastroenterology: official journal of the Digestive Diseases Foundation
Hepatocellular carcinoma (HCC), the most frequent malignant tumour of the liver, is the commonest... more Hepatocellular carcinoma (HCC), the most frequent malignant tumour of the liver, is the commonest cancer occurring in males in the world. The annual incidence of the disease worldwide is estimated to be one million cases. There are variations in its geographical distribution. It tops the list of malignancies amongst males in sub-saharan Africa; it is the second most common cancer in Southeast Asia, including Hong Kong, and ranks third amongst males in China. It is relatively rare in America, Europe North Africa, and the Middle East. During the last 15 years, epidemiologic and laboratory investigations have established a strong and specific association between chronic hepatitis B virus (HBV) infection and HCC. Hepatic cirrhosis is another major aetiologic factor incriminated. In areas with a low incidence of HCC, cirrhosis due to alcohol may be a relatively more important predisposing factor. Chronic non-A, non-B hepatitis (NANBH) infection has now been incriminated as a cause of HCC, especially in Japan. Other environmental factors, particularly chemical carcinogens such as Aflatoxin, smoking, genetic predisposition and sex hormones may also act to promote hepatocarcinogenesis. The exact mechanisms of neoplastic transformation, however, are still far from understood. The following factors are discussed in detail: 1. HBV infection 2. Cirrhosis 3. NANBH infection 4. Aflatoxin B1 5. Cigarette smoking 6. Alcohol A number of less important associated diseases are also listed in Table I. At the end of this paper, a tentative scheme for hepatocarcinogenesis has been proposed and the methods for prevention is discussed in light of the risk factors considered.
alpha-Interferon has been shown to be the most promising antiviral agent in the treatment of chro... more alpha-Interferon has been shown to be the most promising antiviral agent in the treatment of chronic hepatitis B virus infection in Caucasian patients. The experience with recombinant interferon alfa-2a and alfa-2b in four randomized controlled trials in Chinese adults and children is reviewed here. alpha-Interferon alone has little long-term benefit in the treatment of Chinese patients with chronic hepatitis B virus infection, especially in patients who have normal or near normal serum aminotransferase levels. The response in patients with elevated aminotransferase levels appears to be better. The poor antiviral response in patients with normal aminotransferase levels is probably due to immunological tolerance to HBV induced by exposure to the virus in early life. Prednisone pretreatment does not seem to have any additional benefit to using interferon alone in these patients, while the effect in patients with elevated aminotransferase levels remains to be proven.
Pretrial and posttrial liver biopsy samples from 124 adult patients who participated in two rando... more Pretrial and posttrial liver biopsy samples from 124 adult patients who participated in two randomized, controlled trials of interferon alfa therapy for chronic hepatitis B virus (HBV) infection were analyzed to determine the effects of interferon on the replication of HBV in the liver. Replicative forms of HBV DNA were detected in the pretrial biopsy samples from all and posttrial biopsy samples from 74% treated patients and 86% controls. Replicative forms of HBV DNA were detected in the posttrial biopsy samples from all patients who remained positive for hepatitis B e antigen and HBV DNA in the serum, in 77% treated patients and 80% controls who cleared HBV DNA in the serum but who remained positive for hepatitis B e antigen, but in only 19% treated patients and 40% controls who cleared HBV DNA as well as hepatitis B e antigen in the serum. Serum alanine aminotransferase levels were significantly lower in patients whose posttrial biopsies did not contain replicative forms of HBV DNA. In summary, we demonstrated that in most patients with chronic HBV infection treated with interferon alfa, serological response was associated with the disappearance of replicative forms of HBV DNA in the liver.
In a randomized, controlled trial to investigate the possible benefit of insulin and glucagon the... more In a randomized, controlled trial to investigate the possible benefit of insulin and glucagon therapy in severe acute alcoholic hepatitis, 86 patients were randomized to receive 30 U insulin and 3 mg glucagon in 250 ml 5% dextrose over 12 hr each day for 3 wk or a similar regime of identical placebo. No significant differences were seen in patients' clinical characteristics and disease severity in the treated and placebo groups. Of the 43 patients receiving insulin and glucagon, 15 (35%) died within 4 wk of randomization, compared with 14 deaths (33%) in the control patients (p = not significant). When the patients surviving the first 4 wk were examined there were five more deaths in the treatment group, compared with one death in the control group at 6-mo follow-up (p = not significant). No significant differences in the frequency of short-term or long-term complications of alcoholic liver disease or relapse to alcohol were seen when the two groups were compared, although hypoglycemia was seen in six patients during infusion of insulin and glucagon. Similarly, no significant differences were seen in the improvement in clinical or biochemical features at 4 wk and at 6 mo in survivors when the insulin and glucagon-treated patients were compared with patients in the placebo group. This study does not confirm previous reports that insulin and glucagon infusion improves the outcome of severe acute alcoholic hepatitis.
The expression of hepatitis B viral antigens was quantified in liver tissue from four transplant ... more The expression of hepatitis B viral antigens was quantified in liver tissue from four transplant recipients with fibrosing cholestatic hepatitis (FCH) and compared with five other transplant recipients who did not develop this syndrome and 30 patients with chronic hepatitis B virus (HBV) infection. As measured by radioimmunoassays, the liver tissue from patients with FCH had significantly greater amounts of both hepatitis B surface antigen (HBsAg) and nucleocapsid antigens than to transplant patients without this syndrome (P less than 0.01) or patients with chronic HBV infection (P less than 0.001). Intrahepatic expression of pre-S1/pre-S2 in FCH was also extensive with a distribution parallel to that of HBsAg. High-level expression of intrahepatic HBsAg and hepatitis B core antigen in the explanted liver was associated with subsequent development of FCH in the liver graft, suggesting that viral/host factors may also be important. This pattern of intrahepatic hepatitis viral antigen expression, by analogy with Chisari's transgenic mice model and Roingeard's HBV-transfected HepG2 cell model, may be the cause of direct hepatocytopathic injury in this condition.
To determine whether a priming course of lymphoblastoid interferon-alpha (IFN-alpha) enhances the... more To determine whether a priming course of lymphoblastoid interferon-alpha (IFN-alpha) enhances the efficacy of subsequent IFN-alpha therapy in the treatment of chronic hepatitis B, a randomized trial was conducted to compare IFN-alpha priming (IFN-alpha for one month; no treatment for one month) followed by IFN-alpha therapy for three months, with IFN-alpha therapy (10 MU thrice-weekly) given for three months. Thirty-seven patients seropositive for more than six months for HBsAg, HBeAg and HBV DNA, and with histological evidence of active liver inflammation, were recruited. Eight patients (40%) treated with a priming course of IFN-alpha responded to subsequent IFN-alpha therapy for three months with loss of HBV DNA and HBe seroconversion. This compared with five patients (29%), treated only with IFN-alpha therapy for three months, who lost HBV DNA and HBeAg (but only two [12%] developed anti-HBe). IFN-alpha was well tolerated, with only three patients withdrawing from the study because of 'flu'-like symptoms or inconvenience in the early phase. The better response, although not significant, may suggest a place for a short priming course of IFN-alpha in addition to the current IFN-alpha treatment regimen.
To evaluate the histologic effects of interferon-alpha (IFN alpha) therapy on chronic hepatitis B... more To evaluate the histologic effects of interferon-alpha (IFN alpha) therapy on chronic hepatitis B virus (HBV) infection, a semiquantitative study using a modified Knodell's numeric histologic scoring system was performed on paired pre- and post-treatment liver biopsy specimens from 127 adult Chinese patients from two trials of IFN alpha therapy (IFN alpha, n = 86; control, n = 41). The effects of IFN alpha therapy on the hepatic expression of HBV antigens were also determined using immunohistochemical analysis. Serologic response with clearance of HBV e antigen (n = 18) was associated with reduction in lobular activity, periportal piecemeal necrosis, portal inflammation, and total histologic scores. Loss of HBV e antigen also was associated with a reduction in the amount of HBV core antigen in the hepatocytes. In contrast, there was an increase in hepatic expression of HBV surface antigen after IFN alpha therapy. Patients who lost HBV e antigen with IFN alpha therapy were characterized by more severe initial periportal piecemeal necrosis before treatment. These data indicate that (1) serologic response is associated with a reduction in hepatic HBV replication and an improvement in hepatic histology, and (2) patients with severe periportal piecemeal necrosis respond more favorably to IFN alpha therapy.
... The clinical data, HBV markers and liver histology of these patients are tabulated in Table 1... more ... The clinical data, HBV markers and liver histology of these patients are tabulated in Table 1. Correspondence: Dr. Johnson YN Lau ... 12 Lau JYN, Sheron N, Morris AG, Bomford AB, Alexander GJM, Williams R. Interferonalpha receptor expression and regulation in chronic ...
Serial liver biopsy specimens from 11 patients who had liver transplants after hepatitis D virus ... more Serial liver biopsy specimens from 11 patients who had liver transplants after hepatitis D virus (HDV)-related end-stage liver disease developed were examined, allowing a novel opportunity to study the evolution of HDV infection in relation to hepatitis B virus (HBV) infection from the earliest stages. Hepatitis D virus antigen was detected in liver tissue in the absence of either tissue or serologic evidence of HBV recurrence within 3 months in all eight patients biopsied at that time. After serologic evidence of recurrent HBV infection in nine patients, there was a massive increase in hepatic expression of hepatitis D virus antigen and this was associated with the transient appearance of serum hepatitis D virus antigen in four patients. Coexpression of both HBV and HDV antigens in the liver was associated with the onset of lobular hepatitis, which progressed to chronic hepatitis in five patients. These findings indicate that HDV can survive and synthesize HDAg in the absence of detectable HBV, but when HBV replication increased to a detectable level, HDV replication was enhanced massively. Contrary to current thinking, the data suggest that HDV is not directly cytopathic and that HBV is an essential cofactor in the evolution of hepatocellular damage.
Hepatic cellular and subcellular expression of hepatitis B virus (HBV) antigens--HBsAg, HBcAg, an... more Hepatic cellular and subcellular expression of hepatitis B virus (HBV) antigens--HBsAg, HBcAg, and HBeAg--in 143 Chinese patients with chronic HBV infection were studied by immunohistochemical techniques. Nuclear expression of HBcAg and nuclear and cytoplasmic expression of HBeAg showed a secular trend decreasing from the carrier state and chronic persistent hepatitis (CPH), through chronic active hepatitis (CAH), to cirrhosis with or without hepatocellular carcinoma. In contrast, cytoplasmic HBcAg expression was significantly greater in patients with CPH and CAH (P < .0108). In addition, cytoplasmic HBcAg correlated significantly with lobular activity, portal inflammation, and hepatitic activity (P < or = .007). Expression of cytoplasmic HBcAg also exceeded cytoplasmic HBeAg and nuclear HBcAg in liver specimens showing significant damage (P < .038). HBsAg, however, showed no secular trend and was not related to liver histology. The authors' findings support the theory that HBcAg is also the viral target antigen for immune-mediated liver damage in Chinese patients with chronic HBV infection.
To determine the effect of immunosuppressive therapy on hepatic expression of hepatitis B virus (... more To determine the effect of immunosuppressive therapy on hepatic expression of hepatitis B virus (HBV) DNA and antigens in vivo, serial biopsies from 12 patients with chronic active hepatitis B who had been given immunosuppressive therapy (prednisolone 10-15 mg +/- azathioprine 75-125 mg daily) in an earlier period were studied using immunohistochemistry and non-isotopic in situ hybridization. Four out of the 12 patients were positive for hepatic HBcAg/HBeAg/HBV DNA before immunosuppressive therapy. In these 4 patients positive for HBcAg, there was an increase in staining intensity and the proportion of liver cells positive for both HBcAg/HBeAg/HBV DNA and HBsAg during therapy. Of the 8 patients negative for hepatic HBcAg/HBeAg/HBV DNA before immunosuppressive therapy, hepatic HBcAg, HBeAg, and HBV DNA were detected in 2 patients, along with stronger and more diffuse hepatic expression of HBsAg. The other 6 patients also had an increase in hepatic HBsAg expression but without HBcAg. These data provide in vivo evidence that in some patients, immunosuppressive therapy enhances hepatic expression of both HBV genome and gene products.
1. Gastroenterology. 1994 Oct;107(4):1181-2. Molecular evolutionary virology: its application to ... more 1. Gastroenterology. 1994 Oct;107(4):1181-2. Molecular evolutionary virology: its application to hepatitis C virus. Mizokami M, Gojobori T, Lau JY. Second Department of Medicine, Nagoya City University Medical School, Japan. PMID: 7926467 [PubMed - indexed for MEDLINE]. ...
Current definitions of response to interferon (IFN) depend upon decreasing the serum alanine amin... more Current definitions of response to interferon (IFN) depend upon decreasing the serum alanine aminotransferase (ALT) level to normal during therapy. Although this complete response is often associated with loss of detectable hepatitis C virus (HCV) in serum, the frequent occurrence of relapse indicates that eradication of the virus is not achieved. Thus, consideration of more meaningful end points for IFN response is necessary. To begin to define a more effective end point, we recently tested serial serum samples from 15 patients with three different biochemical response patterns (five patients, no response; five, complete response with relapse; five, complete and sustained response) for HCV-RNA by both reverse transcription polymerase chain reaction (RT-PCR) and branched DNA signal amplification assay. In the IFN nonrespondes, HCV-RNA was detected in serum and liver at completion of IFN therapy in all five patients. Similarly, in the complete responders followed by relapse, HCV-RNA was still detected in serum and liver at the end of IFN therapy in four and five patients, respectively, despite complete normalization of serum ALT. In the complete and sustained responders, HCV-RNA was detected in serum and liver at completion of IFN therapy in only one and no patients, respectively. However, all five sustained biochemical responders had virologic relapse detected at one or more time points within 6 months after cessation of IFN therapy despite persistently normal ALT. HCV-RNA remained detectable in serum at the pretreatment level without biochemical abnormalities for a range of 1 1/4 to 3 years.(ABSTRACT TRUNCATED AT 250 WORDS)
Tropical gastroenterology: official journal of the Digestive Diseases Foundation
Hepatocellular carcinoma (HCC), the most frequent malignant tumour of the liver, is the commonest... more Hepatocellular carcinoma (HCC), the most frequent malignant tumour of the liver, is the commonest cancer occurring in males in the world. The annual incidence of the disease worldwide is estimated to be one million cases. There are variations in its geographical distribution. It tops the list of malignancies amongst males in sub-saharan Africa; it is the second most common cancer in Southeast Asia, including Hong Kong, and ranks third amongst males in China. It is relatively rare in America, Europe North Africa, and the Middle East. During the last 15 years, epidemiologic and laboratory investigations have established a strong and specific association between chronic hepatitis B virus (HBV) infection and HCC. Hepatic cirrhosis is another major aetiologic factor incriminated. In areas with a low incidence of HCC, cirrhosis due to alcohol may be a relatively more important predisposing factor. Chronic non-A, non-B hepatitis (NANBH) infection has now been incriminated as a cause of HCC, especially in Japan. Other environmental factors, particularly chemical carcinogens such as Aflatoxin, smoking, genetic predisposition and sex hormones may also act to promote hepatocarcinogenesis. The exact mechanisms of neoplastic transformation, however, are still far from understood. The following factors are discussed in detail: 1. HBV infection 2. Cirrhosis 3. NANBH infection 4. Aflatoxin B1 5. Cigarette smoking 6. Alcohol A number of less important associated diseases are also listed in Table I. At the end of this paper, a tentative scheme for hepatocarcinogenesis has been proposed and the methods for prevention is discussed in light of the risk factors considered.
alpha-Interferon has been shown to be the most promising antiviral agent in the treatment of chro... more alpha-Interferon has been shown to be the most promising antiviral agent in the treatment of chronic hepatitis B virus infection in Caucasian patients. The experience with recombinant interferon alfa-2a and alfa-2b in four randomized controlled trials in Chinese adults and children is reviewed here. alpha-Interferon alone has little long-term benefit in the treatment of Chinese patients with chronic hepatitis B virus infection, especially in patients who have normal or near normal serum aminotransferase levels. The response in patients with elevated aminotransferase levels appears to be better. The poor antiviral response in patients with normal aminotransferase levels is probably due to immunological tolerance to HBV induced by exposure to the virus in early life. Prednisone pretreatment does not seem to have any additional benefit to using interferon alone in these patients, while the effect in patients with elevated aminotransferase levels remains to be proven.
Pretrial and posttrial liver biopsy samples from 124 adult patients who participated in two rando... more Pretrial and posttrial liver biopsy samples from 124 adult patients who participated in two randomized, controlled trials of interferon alfa therapy for chronic hepatitis B virus (HBV) infection were analyzed to determine the effects of interferon on the replication of HBV in the liver. Replicative forms of HBV DNA were detected in the pretrial biopsy samples from all and posttrial biopsy samples from 74% treated patients and 86% controls. Replicative forms of HBV DNA were detected in the posttrial biopsy samples from all patients who remained positive for hepatitis B e antigen and HBV DNA in the serum, in 77% treated patients and 80% controls who cleared HBV DNA in the serum but who remained positive for hepatitis B e antigen, but in only 19% treated patients and 40% controls who cleared HBV DNA as well as hepatitis B e antigen in the serum. Serum alanine aminotransferase levels were significantly lower in patients whose posttrial biopsies did not contain replicative forms of HBV DNA. In summary, we demonstrated that in most patients with chronic HBV infection treated with interferon alfa, serological response was associated with the disappearance of replicative forms of HBV DNA in the liver.
In a randomized, controlled trial to investigate the possible benefit of insulin and glucagon the... more In a randomized, controlled trial to investigate the possible benefit of insulin and glucagon therapy in severe acute alcoholic hepatitis, 86 patients were randomized to receive 30 U insulin and 3 mg glucagon in 250 ml 5% dextrose over 12 hr each day for 3 wk or a similar regime of identical placebo. No significant differences were seen in patients' clinical characteristics and disease severity in the treated and placebo groups. Of the 43 patients receiving insulin and glucagon, 15 (35%) died within 4 wk of randomization, compared with 14 deaths (33%) in the control patients (p = not significant). When the patients surviving the first 4 wk were examined there were five more deaths in the treatment group, compared with one death in the control group at 6-mo follow-up (p = not significant). No significant differences in the frequency of short-term or long-term complications of alcoholic liver disease or relapse to alcohol were seen when the two groups were compared, although hypoglycemia was seen in six patients during infusion of insulin and glucagon. Similarly, no significant differences were seen in the improvement in clinical or biochemical features at 4 wk and at 6 mo in survivors when the insulin and glucagon-treated patients were compared with patients in the placebo group. This study does not confirm previous reports that insulin and glucagon infusion improves the outcome of severe acute alcoholic hepatitis.
The expression of hepatitis B viral antigens was quantified in liver tissue from four transplant ... more The expression of hepatitis B viral antigens was quantified in liver tissue from four transplant recipients with fibrosing cholestatic hepatitis (FCH) and compared with five other transplant recipients who did not develop this syndrome and 30 patients with chronic hepatitis B virus (HBV) infection. As measured by radioimmunoassays, the liver tissue from patients with FCH had significantly greater amounts of both hepatitis B surface antigen (HBsAg) and nucleocapsid antigens than to transplant patients without this syndrome (P less than 0.01) or patients with chronic HBV infection (P less than 0.001). Intrahepatic expression of pre-S1/pre-S2 in FCH was also extensive with a distribution parallel to that of HBsAg. High-level expression of intrahepatic HBsAg and hepatitis B core antigen in the explanted liver was associated with subsequent development of FCH in the liver graft, suggesting that viral/host factors may also be important. This pattern of intrahepatic hepatitis viral antigen expression, by analogy with Chisari's transgenic mice model and Roingeard's HBV-transfected HepG2 cell model, may be the cause of direct hepatocytopathic injury in this condition.
To determine whether a priming course of lymphoblastoid interferon-alpha (IFN-alpha) enhances the... more To determine whether a priming course of lymphoblastoid interferon-alpha (IFN-alpha) enhances the efficacy of subsequent IFN-alpha therapy in the treatment of chronic hepatitis B, a randomized trial was conducted to compare IFN-alpha priming (IFN-alpha for one month; no treatment for one month) followed by IFN-alpha therapy for three months, with IFN-alpha therapy (10 MU thrice-weekly) given for three months. Thirty-seven patients seropositive for more than six months for HBsAg, HBeAg and HBV DNA, and with histological evidence of active liver inflammation, were recruited. Eight patients (40%) treated with a priming course of IFN-alpha responded to subsequent IFN-alpha therapy for three months with loss of HBV DNA and HBe seroconversion. This compared with five patients (29%), treated only with IFN-alpha therapy for three months, who lost HBV DNA and HBeAg (but only two [12%] developed anti-HBe). IFN-alpha was well tolerated, with only three patients withdrawing from the study because of 'flu'-like symptoms or inconvenience in the early phase. The better response, although not significant, may suggest a place for a short priming course of IFN-alpha in addition to the current IFN-alpha treatment regimen.
To evaluate the histologic effects of interferon-alpha (IFN alpha) therapy on chronic hepatitis B... more To evaluate the histologic effects of interferon-alpha (IFN alpha) therapy on chronic hepatitis B virus (HBV) infection, a semiquantitative study using a modified Knodell's numeric histologic scoring system was performed on paired pre- and post-treatment liver biopsy specimens from 127 adult Chinese patients from two trials of IFN alpha therapy (IFN alpha, n = 86; control, n = 41). The effects of IFN alpha therapy on the hepatic expression of HBV antigens were also determined using immunohistochemical analysis. Serologic response with clearance of HBV e antigen (n = 18) was associated with reduction in lobular activity, periportal piecemeal necrosis, portal inflammation, and total histologic scores. Loss of HBV e antigen also was associated with a reduction in the amount of HBV core antigen in the hepatocytes. In contrast, there was an increase in hepatic expression of HBV surface antigen after IFN alpha therapy. Patients who lost HBV e antigen with IFN alpha therapy were characterized by more severe initial periportal piecemeal necrosis before treatment. These data indicate that (1) serologic response is associated with a reduction in hepatic HBV replication and an improvement in hepatic histology, and (2) patients with severe periportal piecemeal necrosis respond more favorably to IFN alpha therapy.
... The clinical data, HBV markers and liver histology of these patients are tabulated in Table 1... more ... The clinical data, HBV markers and liver histology of these patients are tabulated in Table 1. Correspondence: Dr. Johnson YN Lau ... 12 Lau JYN, Sheron N, Morris AG, Bomford AB, Alexander GJM, Williams R. Interferonalpha receptor expression and regulation in chronic ...
Serial liver biopsy specimens from 11 patients who had liver transplants after hepatitis D virus ... more Serial liver biopsy specimens from 11 patients who had liver transplants after hepatitis D virus (HDV)-related end-stage liver disease developed were examined, allowing a novel opportunity to study the evolution of HDV infection in relation to hepatitis B virus (HBV) infection from the earliest stages. Hepatitis D virus antigen was detected in liver tissue in the absence of either tissue or serologic evidence of HBV recurrence within 3 months in all eight patients biopsied at that time. After serologic evidence of recurrent HBV infection in nine patients, there was a massive increase in hepatic expression of hepatitis D virus antigen and this was associated with the transient appearance of serum hepatitis D virus antigen in four patients. Coexpression of both HBV and HDV antigens in the liver was associated with the onset of lobular hepatitis, which progressed to chronic hepatitis in five patients. These findings indicate that HDV can survive and synthesize HDAg in the absence of detectable HBV, but when HBV replication increased to a detectable level, HDV replication was enhanced massively. Contrary to current thinking, the data suggest that HDV is not directly cytopathic and that HBV is an essential cofactor in the evolution of hepatocellular damage.
Hepatic cellular and subcellular expression of hepatitis B virus (HBV) antigens--HBsAg, HBcAg, an... more Hepatic cellular and subcellular expression of hepatitis B virus (HBV) antigens--HBsAg, HBcAg, and HBeAg--in 143 Chinese patients with chronic HBV infection were studied by immunohistochemical techniques. Nuclear expression of HBcAg and nuclear and cytoplasmic expression of HBeAg showed a secular trend decreasing from the carrier state and chronic persistent hepatitis (CPH), through chronic active hepatitis (CAH), to cirrhosis with or without hepatocellular carcinoma. In contrast, cytoplasmic HBcAg expression was significantly greater in patients with CPH and CAH (P < .0108). In addition, cytoplasmic HBcAg correlated significantly with lobular activity, portal inflammation, and hepatitic activity (P < or = .007). Expression of cytoplasmic HBcAg also exceeded cytoplasmic HBeAg and nuclear HBcAg in liver specimens showing significant damage (P < .038). HBsAg, however, showed no secular trend and was not related to liver histology. The authors' findings support the theory that HBcAg is also the viral target antigen for immune-mediated liver damage in Chinese patients with chronic HBV infection.
To determine the effect of immunosuppressive therapy on hepatic expression of hepatitis B virus (... more To determine the effect of immunosuppressive therapy on hepatic expression of hepatitis B virus (HBV) DNA and antigens in vivo, serial biopsies from 12 patients with chronic active hepatitis B who had been given immunosuppressive therapy (prednisolone 10-15 mg +/- azathioprine 75-125 mg daily) in an earlier period were studied using immunohistochemistry and non-isotopic in situ hybridization. Four out of the 12 patients were positive for hepatic HBcAg/HBeAg/HBV DNA before immunosuppressive therapy. In these 4 patients positive for HBcAg, there was an increase in staining intensity and the proportion of liver cells positive for both HBcAg/HBeAg/HBV DNA and HBsAg during therapy. Of the 8 patients negative for hepatic HBcAg/HBeAg/HBV DNA before immunosuppressive therapy, hepatic HBcAg, HBeAg, and HBV DNA were detected in 2 patients, along with stronger and more diffuse hepatic expression of HBsAg. The other 6 patients also had an increase in hepatic HBsAg expression but without HBcAg. These data provide in vivo evidence that in some patients, immunosuppressive therapy enhances hepatic expression of both HBV genome and gene products.
1. Gastroenterology. 1994 Oct;107(4):1181-2. Molecular evolutionary virology: its application to ... more 1. Gastroenterology. 1994 Oct;107(4):1181-2. Molecular evolutionary virology: its application to hepatitis C virus. Mizokami M, Gojobori T, Lau JY. Second Department of Medicine, Nagoya City University Medical School, Japan. PMID: 7926467 [PubMed - indexed for MEDLINE]. ...
Current definitions of response to interferon (IFN) depend upon decreasing the serum alanine amin... more Current definitions of response to interferon (IFN) depend upon decreasing the serum alanine aminotransferase (ALT) level to normal during therapy. Although this complete response is often associated with loss of detectable hepatitis C virus (HCV) in serum, the frequent occurrence of relapse indicates that eradication of the virus is not achieved. Thus, consideration of more meaningful end points for IFN response is necessary. To begin to define a more effective end point, we recently tested serial serum samples from 15 patients with three different biochemical response patterns (five patients, no response; five, complete response with relapse; five, complete and sustained response) for HCV-RNA by both reverse transcription polymerase chain reaction (RT-PCR) and branched DNA signal amplification assay. In the IFN nonrespondes, HCV-RNA was detected in serum and liver at completion of IFN therapy in all five patients. Similarly, in the complete responders followed by relapse, HCV-RNA was still detected in serum and liver at the end of IFN therapy in four and five patients, respectively, despite complete normalization of serum ALT. In the complete and sustained responders, HCV-RNA was detected in serum and liver at completion of IFN therapy in only one and no patients, respectively. However, all five sustained biochemical responders had virologic relapse detected at one or more time points within 6 months after cessation of IFN therapy despite persistently normal ALT. HCV-RNA remained detectable in serum at the pretreatment level without biochemical abnormalities for a range of 1 1/4 to 3 years.(ABSTRACT TRUNCATED AT 250 WORDS)
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