The aim of this study was to analyze the clinical performance of a new enzyme immunoassay (EIA) for hepatitis C virus (HCV) core antigen in comparison with the reverse transcription polymerase chain reaction (RT-PCR).A total of 310 patients with acute or chronic hepatitis C, and 132 HCV-negative controls were studied. Chemiluminescence EIA with monoclonal anti-HCV core antigen was used, and qualitative and quantitative commercial RT-PCRs and an in-house nested RT-PCR were performed. Compared with nested RT-PCR, the core antigen assay showed 97% sensitivity and 100% specificity in 75 patients with chronic hepatitis C and 132 controls. HCV core antigen was positive in 16 (94%) of 17 patients with acute hepatitis C at initial consultation. In 3 persons prospectively followed, core antigen was detected in the first available (1-3 weeks) post-transfusion sample. In 167 anti-HCV-positive individuals, 129 (77%) were viremic; core antigen was detected in 126 (98%) compared with 129 (100%) for nested RT-PCR and 121 (94%) for the commercial RT-PCR. In 48 patients with chronic hepatitis C treated with interferon alfa, the concentration of core antigen before treatment was significantly (P < .002) lower in patients with sustained response than in nonresponders. All responders had a sustained loss of core antigen, whereas all nonresponders remained core antigen positive. The concentrations of HCV core antigen and HCV RNA correlated significantly (n ؍ 48, r ؍ .627, P < .001). In conclusion, the HCV core antigen assay is useful for the diagnosis of acute and chronic hepatitis C, and for predicting and monitoring the effect of interferon alfa treatment. (HEPATOLOGY 2000;32: 388-393.)Hepatitis C virus (HCV) infection is a major cause of acute and chronic hepatitis and may eventuate in cirrhosis and hepatocellular carcinoma. 1-3 Measurement of HCV antibody in serum is widely used for screening of HCV infection. 4,5 However, the additional measurement of HCV RNA is required to confirm the presence of active HCV infection 6,7 because 15% to 20% of persons with anti-HCV have no detectable viremia and are presumed to have recovered. Quantitative measurement of HCV RNA in serum is useful for predicting and monitoring the response to interferon alfa therapy in patients with chronic hepatitis C. 8,9 Qualitative determinations of HCV RNA generally use reverse transcription followed by the polymerase chain reaction (RT-PCR) 10 and, more recently, transcription-mediated amplification. 11 Quantitative determinations are based either on amplification of the target RNA and comparison with RNA standards or signal amplification using branched DNA molecules. Molecular amplification assays, although highly sensitive, have encountered problems with specificity and precision and in blinded comparisons have had significant error rates. 12 Further, the assays are relatively complex for nonresearch settings and are contamination prone and costly. An HCV antigen assay might obviate many of these problems and would have great use in blood screening ...
A highly sensitive enzyme immunoassay (EIA) for the hepatitis C virus (HCV) core antigen (HCVcAg) was developed, and its performance was compared with that of the AMPLICOR HCV test (Roche Molecular Systems). The developed one-step pretreatment method, 30-min incubation of the specimen with a solution containing three different types of detergents (Triton X-100, 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate [CHAPS], and sodium dodecyl sulfate), does not require any special device. Because the interfering anti-core antibody in the sample was sufficiently inactivated by the pretreatment, HCVcAg in the sample could be detected. The immunoreactivity on gel filtration was shifted from void fractions to those corresponding to the molecular mass range from 20 to 25 kDa, which is equal to the estimated molecular mass of HCVcAg, after the pretreatment. By the recovery test with HCVcAg-positive serum, the recovery rate was 93.5 to 106.5%. There was no interference with the EIA by anticoagulants or blood components in the serum. When the cutoff value was tentatively set at 0.5 mU/ml based on the distribution of healthy subjects’ sera, the sera of all healthy subjects (n = 125) and patients with hepatitis B (n = 50) were negative. HCVcAg was detected in sera from 57 of 73 individuals (78.1%) with anti-HCV antibody. Similarly, HCV RNA was detected in sera from 59 individuals (80.8%) with the AMPLICOR HCV as the qualitative test (AMPLICOR HCV test) and in sera from 54 individuals (74.0%) by the AMPLICOR HCV Monitor as the quantitative test (AMPLICOR Monitor test). Concentrations of HCVcAg and HCV RNA (measured by the AMPLICOR Monitor test) correlated significantly (r = 0.8, P < 0.001). On seroconversion panels, HCVcAg was detected during the early stage of infection, when anti-HCV antibodies had not been produced. This assay for HCVcAg is simpler than assays for HCV RNA based on gene technology and shows specificity and sensitivity equivalent to those of the AMPLICOR HCV test.
Although hepatitis C virus (HCV) is a well-known causative agent of hepatocellular carcinoma (HCC),
Aims Hepatitis B surface antigen (HBsAg) seroclearance indicates a “functional cure” in chronic hepatitis B (CHB) virus infection. However, several cases of hepatocellular carcinoma (HCC) development have been reported after HBsAg seroclearance. We evaluated the potential of HBsAg and hepatitis B core‐related antigen (HBcrAg), measured by the ultra‐highly sensitive assays, in cases with HCC development after HBsAg seroclearance. Methods We enrolled 17 patients with CHB who achieved HBsAg seroclearance, defined by the conventional assay using Architect HBsAg QT kit (five HCC patients and 12 non‐HCC patients). HBsAg and HBcrAg were measured in their stored serum samples using ultra‐highly sensitive assays featuring “immunoassay for total antigen including complex via pretreatment (iTACT)” technology. Results All five patients who developed HCC were positive for HBsAg or HBcrAg by iTACT‐HBsAg or iTACT‐HBcrAg at all follow‐up points. HBcrAg levels in the HCC group, using iTACT‐HBcrAg, were significantly higher than those in the non‐HCC group at HBsAg seroclearance (3.6 LogU/ml (2.8–4.2) versus 2.6 (<2.1–3.8), p = 0.020). The best cutoff value of iTACT‐HBcrAg for predicting HCC development was 2.7 LogU/ml by receiver operating characteristic curve analysis. The prevalence of HBcrAg ≥2.7 in the HCC group was significantly higher than that in non‐HCC group (100% [5/5] versus 33% [4/12], p = 0.029). Conclusions Residual low viral antigen might predict HCC development even if HBsAg seroclearance was achieved according to a conventional assay. The results suggest that iTACT assays of HBsAg and HBcrAg would be useful for monitoring CHB patients.
To identify the so‐called toxohormone, which is a tumor‐derived factor with activity to induce cancer cachexla syndrome in tumor‐bearing animals, 5 human cancer cell lines with this activity were studied for cytokine production. Tumor cell products with activity to inhibit lipoprotein lipase (LPL) were shown to play an important role in the development of the cancer cachexia syndrome. All culture media conditioned by the 5 cell lines possessed LPL‐inhibitory activity. However, the activity differed with the cell line. In order to characterize the activity, we examined whether the cultured cells produced cytokines with activity to inhibit LPL. A melanoma cell line, SEKI, and a neuroepithelioma cell line, NAGAI, were found to express a large amount of leukemia inhibitory factor (LIF) mRNA. Furthermore, both of these cell lines were demonstrated to produce a large amount of LIF protein, and plasma levels of LIF were extremely elevated in SEKI‐ and NAGAI‐bearing nude mice, indicating that LIF produced by the tumor cells induced cancer cachexia syndrome in the animals. Thus, LIF fulfills the requirements for a toxohormone, except for suppressive activity on liver catalase. In contrast, the mechanisms responsible for cachexia in the MKN‐1‐, LX‐1‐ and LS180‐bearing mice remain unknown. These findings suggest that various types of bioactive substances produced by cancer cells could be toxohormones.
Toxohormones are tumor-derived factors that induce cancer cachexia syndrome in tumor-bearing animals. Nude mice bearing tumors induced by eight human cancer cell lines with this activity were studied for cytokine production and expression of a newly identified gene, ob, which has the ability to control body weight. A melanoma cell line, SEKI, and a neuroepithelioma cell line, NAGAI, produced a large amount of the cytokine, leukemia-inhibitory factor (LIF). A uterine carcinoma cell line, Yumoto, produced a large amount of interleukin 6 (IL-6), and an oral cavity carcinoma cell line, OCC-1C, concomitantly produced LIF, IL-6, and IL-11. Reverse transcription polymerase chain reaction studies revealed that ob gene mRNA was not expressed in any of these cell lines, suggesting that the gene does not have a role as a tumor product responsible for cancer cachexia in this model. These findings suggest that in four of eight animal models in which cancer cachexia syndrome developed, LIF, IL-6, or possibly IL-11 produced by cancer cells may be toxohormones, but in the remaining four cancer cell lines the mechanism responsible for cachexia syndrome remains unknown.
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