HCV in non-replicative chronic HBV infection.
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Chronic Disease↗
Biomedical subjects
H M Smith
Publications and source records attributed to H M Smith.
Modulation of hepatitis B viral antigen expression by immunosuppressive drugs in primary hepatocyte culture.
In one pattern of hepatitis B virus (HBV) recurrence following orthotopic liver transplantation--namely, fibrosing cholestatic hepatitis (FCH), the intrahepatic expression of HBV antigens was found to be markedly increased, suggesting that HBV may be directly cytopathic to the liver cells. Understanding how immunosuppressive drugs influence HBV may be of considerable clinical relevance in the treatment of patients with chronic HBV infection after liver transplantation. To determine how these drugs influence intrahepatic HBV antigen expression, hepatocytes isolated from patients with chronic HBV infection were incubated in the absence or presence of prednisolone (10(-6)-10(-10) M), methylprednisolone (10(-6)-10(-10) M), azathioprine (0.1-10 micrograms/ml), or cyclosporine (50-1000 ng/ml) and the amount of intracellular/secreted antigen was measured by radioimmunoassay. Intracellular HBsAg increased by 25.0-51.1% with prednisolone 10(-8)-10(-6) M (n = 14, P less than 0.05) and methylprednisolone 10(-9)-10(-6) M (n = 8, P less than 0.05). Immunocytochemistry of cytospins showed that the proportion of cells containing HBsAg increased by 20-38% with stronger staining, but the distribution of HBsAg remained diffusely cytoplasmic; the changes in intracellular pre-S1 and pre-S2 paralleled those of HBsAg. Secreted HBsAg was, however, not affected. There was also an increase in intracellular nucleocapsid antigens by 24.1-32.5% with an increase in hepatocytes containing nucleocapsid antigens by 8-18%. Methylprednisolone exerted similar effects to prednisolone. On the other hand, neither azathioprine (n = 11) nor cyclosporine (n = 12) had any effect on intracellular or secreted HBsAg or nucleocapsid antigens. These data indicate that corticosteroids, but not azathioprine or cyclosporine, enhance intracellular HBV antigen expression in this short-term culture system. This may be an important factor in the evolution of FCH and careful attention to the use of corticosteroids may be beneficial in patients with chronic HBV infection undergoing liver transplantation.
Adult↗
Hepatitis B and delta virus infection among "at risk" populations in south east London.
STUDY OBJECTIVE: The hepatitis delta virus (HDV) contributes significantly to the morbidity and mortality of hepatitis B virus (HBV) infection, which is particularly prevalent among intravenous drug users and male homosexuals. A recent report has indicated that HDV first appeared in the South East London intravenous drug using population in 1982. The aim of the present study was to assess the prevalence of HDV in these two groups at risk of HBV infection in South East London. DESIGN: The study was a cohort analysis of HBV and delta virus serum markers, stratified temporally and with respect to intravenous drug use and sexual practice. SETTING: This was a population study of 372 consecutive intravenous drug users attending a local drug rehabilitation centre and 1481 subjects seen at a sexually transmitted disease clinic in the same area, during the years 1979 to 1988. MEASUREMENTS AND MAIN RESULTS: Of 372 intravenous drug users, 195 (52.4%) had evidence of current or past infection with HBV, of whom 17 had chronic HBV infection--a carriage rate of 8.7%. Twelve (70.6%) of these 17 also had chronic HDV infection--the first cases being identified in 1984. By comparison, 406 (27.4%) of the sexually transmitted disease clinic patients had been been exposed to HBV, 32 having chronic HBV: a carriage rate of 7.9% (7.5% v 9.4% among male homosexuals v male heterosexuals). Ten had been exposed to HDV (the first case in 1980) but only two (who did not admit to intravenous drug use) had chronic HDV infections (p less than 0.0005 v the rehabilitation centre patients). CONCLUSIONS: Although the HBV carriage rate is very similar in these two populations, chronic HDV infections were mainly confined to intravenous drug users. However, reports from the USA and France indicate spread of delta virus to the male homosexual community and, since there is clearly a pool of HDV in SE London, vaccination against HBV in these risk groups in likely to be cost-effective and should be actively encouraged.
Female↗
Antibodies to hepatitis C virus in autoimmune liver disease: evidence for geographical heterogeneity.
To resolve conflicting reports about the occurrence of antibodies against hepatitis C virus (HCV) in patients with autoimmune chronic active hepatitis (AI-CAH), sera from UK and Italian patients were tested with the original anti-HCV assay (Ortho) and a novel anti-HCV assay (UBI) based entirely on synthetic HCV peptides. 28 (60%) of 47 Italian patients with type-1 AI-CAH were anti-HCV-positive by Ortho ELISA, 25 of whom were also strongly positive by the UBI assay. 15 (60%) of 25 UK patients with type-1 AI-CAH were HCV-positive by Ortho ELISA but only 2 were positive by the UBI assay. Similarly, 29 (88%) of 33 Italian patients with type-2 AI-CAH, but 0 of 10 UK patients, were very strongly anti-HCV-positive with the UBI assay. Italian patients with AI-CAH appear to have a high frequency of genuine exposure to HCV, whereas seropositivity by the Ortho HCV ELISA in UK patients is likely to represent a false-positive result. These findings indicate important geographical and/or genetic influences in autoimmune liver disease among different populations.
Adult↗
Significance of IgM anti-hepatitis D virus (HDV) in chronic HDV infection.
Intrahepatic hepatitis D virus (HDV) antigen (HDAg) and serum HDV RNA are excellent markers of active HDV replication but the relation of IgM anti-HDV to HDV replication and histological activity is less certain. To further elucidate the significance of serum IgM anti-HDV, 90 paired sera and liver biopsies from 64 patients seropositive for total antibody to HDV were analysed for IgM anti-HDV, intrahepatic HDAg expression, and histological inflammatory activity. IgM anti-HDV was strongly associated with intrahepatic HDAg expression with a sensitivity of 94.1% but the assay lacked specificity since 14 out of 22 cases negative for intrahepatic HDAg were also positive for IgM anti-HDV. In 20 patients in whom follow-up biopsies and paired sera were available, two patients lost intrahepatic HDAg but paired serum remained IgM anti-HDV positive. Although the presence of serum IgM anti-HDV correlated significantly with a higher histological inflammatory activity (P = 0.001), there was a considerable overlap with the group seronegative for IgM anti-HDV, again indicating a poor specificity. This lack of specificity of IgM anti-HDV for both HDV replication and histological activity indicates that this assay provides no additional information over and above assay for total antibody to HDV.
Antigens, Viral↗
An enzyme immunoassay for detection of IgA class antibodies against hepatitis delta virus.
A sensitive and reproducible enzyme-linked immunoassay (ELISA) for IgA class antibodies against the Delta antigen (HDAg) is described. Specificity of the assay was demonstrated by the absence of binding to an unrelated antigen or to uncoated plates and the finding that binding to HDAg was independent of total IgA concentrations in sera. Positive results were obtained with sera from 11 of 14 patients with chronic Delta virus infection (seropositive for HBsAg and IgM anti-HDAg, negative for IgM anti-HBc) at serum dilutions of up to 1:10(6). Sera from four normal healthy individuals and from 25 patients with chronic hepatitis B or other liver disorders who had no evidence of exposure to HDV were all negative in the assay.
Adult↗
Expression of intrahepatic hepatitis D viral antigen in chronic hepatitis D virus infection.
To elucidate the biological importance of intrahepatic hepatitis D virus antigen, its expression was correlated with biochemical and histological inflammatory activity in 98 biopsy specimens from 68 patients seropositive for total antibody to the virus. Seventy five specimens were positive for intrahepatic nuclear antigen for HDV antigen accompanied by cytoplasmic HDV antigen in only one biopsy specimen. This group had significantly higher serum transaminase activities and inflammatory activity than the remaining cases that were negative for HDV antigen. Among the group positive for HDV antigen, there was no correlation between the proportion of hepatocytes containing HDV antigen and either serum transaminase activity or histological inflammatory indices. In 22 HDV antigen positive patients who had follow up biopsy specimens taken at a median of two years, the proportion with cirrhosis increased from 36% to 73%. Serum transaminase activities remained the same during this period, but the proportion of HDV antigen positive cells dropped. Follow up of 51 patients showed that 21 died or underwent liver transplantation within three years. The absence of an association between intrahepatic HDV antigen expression and progression of histological liver damage does not support the view that HDV is directly cytopathic to hepatocytes. Immune mediated mechanisms may have a role in the pathogenesis of chronic liver disease related to HDV infection.
Adult↗
Frequency of asymptomatic hepatitis types B and C in an inner city community and relation to possible risk factors.
The frequency of asymptomatic carriage of the hepatitis virus types B and C in an inner city area (South London) was assessed in a survey of 1002 subjects attending their General Practitioner for minor, non-hepatic complaints. Ten subjects were seropositive for hepatitis B surface antigen (HBsAg) (1 per cent), but only one, who declined liver biopsy, had any clinical laboratory evidence of hepatitis B virus-related chronic liver disease. Carriage of, and exposure to, hepatitis B virus was significantly more frequent among people born outside the UK/Eire and those with a history of jaundice. Among people of Caribbean origin the frequency of hepatitis B virus markers fell from 31 per cent among those born in the Caribbean to 11 per cent amongst second generation subjects born in this country. Despite careful counselling, offers of further investigation and treatment of those affected, and vaccination of vulnerable children or partners, were often declined. Four percent of the same population had antibodies to the hepatitis C virus using the Ortho anti-hepatitis C virus enzyme-linked immunosorbent assay but this figure fell to 0.9 per cent when a second test, based on synthetic peptides rather than a recombinant antigen, was used. None had any abnormality of standard liver function tests. Chronic asymptomatic carriage of hepatitis, particularly in inner city areas, may be more common than previously recognized. Effective use of antiviral agents and vaccination will be limited until appropriate health education dispels the widespread misconceptions and fears associated with a diagnosis of chronic viral hepatitis.
Adult↗
Effect of interferon-gamma on hepatitis B viral antigen expression in primary hepatocyte culture.
Interferon-alpha has been shown recently to selectively enhance hepatocyte expression of HBsAg/pre-S2 in chronic hepatitis B virus infection in a way that may enhance immune recognition. To determine the effect of interferon-gamma on hepatitis B virus antigen expression, hepatocytes isolated from patients with chronic hepatitis B virus infection were incubated in the absence or presence of interferon-gamma and viral antigen expression was assessed by both radioimmunoassay and immunocytochemistry using appropriate monoclonal antibodies. Interferon-gamma inhibited the expression of all hepatitis B virus antigens tested. Intracellular HBsAg measured by radioimmunoassay of sonicated hepatocytes fell by 29% with 1 U/ml (p less than 0.01) and 36% with 10 U/ml of interferon-gamma (p less than 0.001) compared with control treatment. Secreted HBsAg was reduced by 19% with 10 U/ml of interferon-gamma (p less than 0.01). Intracellular HBeAg was also decreased by 29% with 1 U/ml (p less than 0.05) and 42% with 10 U/ml of interferon-gamma (p less than 0.05), but no significant change was found in the amount of secreted HBeAg. The proportion of hepatocytes containing various hepatitis B virus antigens and the intracellular viral antigen staining densities also fell significantly with interferon-gamma incubation. Interestingly, the addition of interferon-gamma abolished the augmenting effect of interferon-alpha on intracellular HBsAg. These data indicate that interferon-gamma, in contrast to interferon-alpha, has an inhibitory effect on hepatocyte expression of all hepatitis B virus antigens including HBsAg/pre-S2, suggesting that this may be one factor that accounts for their difference in clinical activity in patients with chronic hepatitis B virus infection.
Cells, Cultured↗
IgA class antibodies to hepatitis delta virus antigen in acute and chronic hepatitis delta virus infections.
Sera from 31 patients with chronic hepatitis delta virus infection and 18 patients with acute hepatitis delta virus infection were examined for IgA class antibodies to this virus using a newly developed enzyme immunoassay. IgA antibody to hepatitis D virus was detected in 21 (67.7%) of 31 patients with chronic delta viral hepatitis, but in only 1 (5.6%) of the 18 patients with acute infection (p less than 0.0005). Of the 21 patients with chronic delta hepatitis with IgA antibody to hepatitis D virus, 19 (90.5%) had moderate-to-severe activity on liver biopsy: 18 of the 21 had histological features of chronic active hepatitis and three had chronic lobular hepatitis. In all, 23 patients with chronic delta hepatitis had moderate-to-severe activity, and 19 (82.6%) had IgA antibody to hepatitis D virus. No statistically significant correlations were found between IgA antibody to hepatitis D virus and biochemical markers of liver injury (p greater than 0.4), or the presence of hepatitis delta virus antigen in liver biopsies (p greater than 0.2), in the patients with chronic delta hepatitis. The finding that IgA antibody to hepatitis D virus was almost exclusively associated with chronic hepatitis delta virus infection and correlated independently with moderate-to-severe histological activity (with a specificity of 90.5% and a sensitivity of 82.6%) suggests that this antibody might be a useful serological marker of underlying liver damage in chronic delta hepatitis.
Acute Disease↗
Detection of hepatitis B virus DNA sequences in liver in HBsAg seronegative patients with liver disease with and without anti-HBc antibodies.
Excluding studies from Brechot and co-workers, little support has been found for a role of the hepatitis B virus in the pathogenesis of HBsAg seronegative patients with predominantly chronic liver diseases, including primary liver cancer. In this study liver DNA from 59 predominantly British patients (four cases with paired biopsies, 6-12 months apart) with different, mostly chronic, liver diseases was analysed by molecular hybridization. All were seronegative for HBsAg and serum hepatitis B virus DNA (dot blot hybridization) and their liver diseases were believed to be unrelated to hepatitis B virus infection. Hepatitis B virus DNA was detected in liver of 11 (18.6 per cent) patients; nine had episomal (3.2 Kb) DNA and eight had higher molecular weight bands suggesting integrated forms. Six patients were also seronegative for anti-HBc. Patients of UK and non-UK origin were equally represented. Hepatitis B virus DNA was detected in serum of six of nine patients tested using the polymerase chain reaction. The detection of hepatitis B virus DNA in liver and in serum by this assay in a significant proportion of patients with chronic liver disease, hitherto unsuspected of being hepatitis B virus-related, suggests a possible role for this virus in low- as well as high-prevalence countries.
Adult↗
Hepatitis C virus antibodies in chronic active hepatitis: pathogenetic factor or false-positive result?
An enzyme immunoassay (Ortho-HCV ELISA) for antibodies against the hepatitis C virus (HCV) was used to test 143 serum samples from 53 patients with autoimmune chronic active hepatitis (AI-CAH). Optical density (OD) values in the assay correlated closely with serum globulin (r = 0.8846, p much less than 0.0005) and IgG (r = 0.6281, p less than 0.0005) concentrations but not with immunosuppressant therapy. OD values were positive in 20 (65%) of 31 with active disease and in only 1 (5%) of 22 in remission (p less than 0.0005). The association between positive results and active disease and high serum globulin levels was confirmed by serial studies in 6 of the patients. In contrast, none of 31 patients with primary biliary cirrhosis and only 2 of 24 with non-hepatic disorders associated with high IgG concentrations were positive, and these controls showed no correlation between OD values and serum globulins or IgG. The findings suggest that serum from AI-CAH patients may contain a component that gives false-positive results in the assay.
Absorption↗
Oviductal, not oviducal.
Both etymologically and in literal meaning the term "oviductal" is overwhelmingly preferable to "oviducal."
Animals↗
A self-contained life support system designed for use with a portable hyperbaric chamber.
Recently, the Gamow Bag, a portable hyperbaric chamber, has been demonstrated to relieve the symptoms of acute mountain sickness (AMS). The patient is completely enclosed in the bag which is inflated and pressurized to simulate descent in altitude. CO2 produced by the patient is vented from the airtight bag by means of a pressure relief valve, while fresh air is brought in from the outside via a high volume foot pump. In order to eliminate the vigorous pumping that is necessary to maintain a suitable atmosphere in the bag, we have designed a completely portable, self-contained life support system that supplies oxygen as it is consumed and removes the waste CO2 as it is produced. The entire rebreathing unit, which maintains a homeostatic atmosphere in the chamber for six to eight hours weighs less than six pounds. The chamber with the self-contained life support system weights less than 18 pounds. It would find its greatest use in medical mountain clinics, isolated ski areas and should become standard equipment for mountain search and rescue units.
Altitude Sickness↗
Clearance of pre-S2 antigen: a marker of successful interferon therapy in hepatitis B virus infection.
The relation between viral replication, the presence of HBsAg and pre-S2 in serum and eventual clinical outcome has been investigated in fourteen patients undergoing treatment with lymphoblastoid interferon for chronic hepatitis B virus (HBV) infection. In four patients permanent loss of pre-S2 was accompanied by loss of serum HBV-DNA in association with a marked elevation of serum aspartate aminotransferase activity and in each of these cases HBsAg was subsequently cleared from serum. In contrast there was no significant fluctuation in the concentration of either pre-S2 or HBsAg in four cases not responding to therapy although substantial or complete inhibition of viral replication had been observed during treatment. In the third group, permanent loss of HBV-DNA was observed but in these cases pre-S2 and HBsAg persisted in serum, albeit at lower concentrations, while in this group loss of HBV-DNA from serum was not accompanied by a flare in disease activity. These results suggest first, that assay of pre-S2 is a further measure of the response to interferon and second that in some cases interferon enhances immune recognition of both the pre-S2 and HBsAg polypeptides.
Adult↗
Elevation of serum sex hormone-binding globulin in females with fulminant hepatitis B virus infection.
Amongst adults exposed to the hepatitis B virus (HBV), the infection pursues a fulminant course more frequently in females, while conversely a chronic carrier state is more frequent in males. Because of these differences in sex ratio, we investigated the relationship between the outcome of HBV infection and serum concentrations of sex hormone-binding globulin (SHBG), a circulating glycoprotein that exerts an important influence on the balance of free sex hormones. SHBG levels were significantly elevated in females with fulminant HBV infection compared to females with either uncomplicated acute or chronic HBV infection (P less than .05 and P less than .001, respectively). That this was not a nonspecific effect of fulminant hepatitis was confirmed by the significantly higher levels in this group than in age-matched females with fulminant hepatitis unrelated to HBV (P less than .05). In contrast, four of 15 female HBsAg carriers had SHBG values in the male range, and these included three of four patients who had acquired HBV as adults. SHBG levels were normal in all male groups. These results suggested that for adults the hormonal environment may be important in determining the course of HBV infection.
Acute Disease↗
Does screening high risk dental patients for hepatitis B virus protect dentists?
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Dentists↗