HBsAg-negative hepatitis B virus infections in hepatitis C virus-associated hepatocellular carcinoma
HBsAg-negative hepatitis B virus infections in hepatitis C virus-associated hepatocellular carcinoma
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DOI：
10.1111/j.1365-2893.2005.00586.x
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发表时间：
2005-05-01
影响因子：
2.5
通讯作者：
Tabor, E
中科院分区：
文献类型：
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作者：
Momosaki, S;Nakashima, Y;Tabor, E
本研究旨在评价在血清中未检测到B型肝炎表面抗原（HBsAg）的肝细胞癌（HCC）患者的血清和/或肿瘤组织中可发现B型肝炎病毒（HBV）DNA序列的报道。这种HBV感染是高度非典型的，因为前瞻性研究表明，在大多数HBV感染期间和之后，特异性血清学标志物有明显的连续性。由于日本大多数HBsAg阴性的HCC患者有丙型肝炎病毒（HCV）感染，因此进行本研究以确定这些患者中是否有未识别的HBV感染。研究了30例来自日本Kurdom的具有丙型肝炎病毒抗体（抗-HCV）的新诊断的HCC患者。30例患者血清中均未检出HBsAg。在22名可获得乙肝B核心抗原抗体（抗-HBc）和HBsAg抗体（抗-HBs）检测结果的患者中，14名（64%）具有抗- HBc和抗-HBs，4名（18%）仅具有抗- HBc，4名（18%）无HBV标志物。采用巢式聚合酶链反应（Nested PCR）检测肝癌组织及癌旁肝组织中HBV表面（S）、核心（C）、聚合酶（P）及核心启动子基因序列。30例患者中有22例（73%）在HCC和/或邻近的非肿瘤性肝脏中检测到HBV DNA [19/30例患者（63%）在HCC和非肿瘤性肝脏中均检测到HBV DNA]。在22例HBV DNA阳性的患者中，10例（46%）检测到一种以上的HBV基因。在4例血清HBV标志物阴性的患者中，3例在HCC和非肿瘤性肝脏（2例）或仅在非肿瘤性肝脏（1例）中有HBV DNA;第4例患者的组织中未检测到HBV DNA。在21例HBV核心启动子序列可检测的患者中，18例（86%）在核心启动子区1762（A-GT）和1764（G-A）核苷酸处均发现突变，未发现与某些HBsAg阴性HBV感染相关的核心启动子区缺失。因此，在22例（73%）HBsAg阴性、抗- HCV阳性的HCC中可检测到HBV DNA，包括3例（10%）抗- HBc和抗-HBs阴性的HCC。在大多数情况下，在核心启动子区的核苷酸1762（A-GT）和1764（G-A）处发现HBV突变，这些突变先前已在整合到HCC DNA中的HBV中报道。在确定HCC病因学关联的血清学调查中，本研究中的患者可能被错误地指定为“HCV相关HCC”，而本研究中的数据表明HBV可能在其HCC的发展中发挥作用。
This study was conducted to evaluate reports that hepatitis B virus (HBV) DNA sequences can be found in the serum and/ or tumour tissue from some hepatocellular carcinoma (HCC) patients who have no detectable hepatitis B surface antigen ( HBsAg) in their sera. Such HBV infections would be highly atypical, because prospective studies have shown a clear succession of specific serologic markers during and after most HBV infections. As most HBsAg- negative HCC patients in Japan have hepatitis C virus (HCV) infections, the present study was conducted to determine whether some of these patients actually have unrecognized HBV infections. Thirty newly diagnosed HCC patients from Kurume, Japan, with antibody to the hepatitis C virus (anti-HCV) were studied. None of the 30 had HBsAg detectable in their serum. Of 22 for whom test results for antibodies to the hepatitis B core antigen (anti-HBc) and antibodies to HBsAg (anti-HBs) were available, 14 (64%) had anti- HBc and antiHBs, four (18%) had anti- HBc alone, and four ( 18%) had no HBV markers. Nested polymerase chain reaction was used to detect the HBV surface ( S), core ( C), polymerase ( P) and core promoter gene sequences in the HCC tissues and in the adjacent nontumorous liver tissues. HBV DNA was detected in HCC and/ or adjacent nontumorous liver in 22 of 30 (73%) patients [ detected in both HCC and nontumorous liver in 19/30 patients (63%)]. Among the 22 patients with detectable HBV DNA, more than one HBV gene was detected in 10 (46%). Among the four patients whose sera were negative for all HBV markers, three had HBV DNA in either HCC and nontumorous liver ( two cases) or only in the nontumorous liver ( one case); HBV DNA could not be detected in tissues from the fourth patient. In 18 of 21 (86%) patients with detectable HBV core promoter sequences, mutations at both nucleotides 1762 ( A - GT) and 1764 ( G - A) in the core promoter region were found. No deletions were detected in the core promoter gene region of the type reported to be associated with some cases of HBsAg- negative HBV infection. Thus, HBV DNA was detectable in 22 ( 73%) HBsAg- negative, anti- HCV- positive HCCs, including three (10%) who were also negative for anti- HBc and anti-HBs. HBV mutations at both nucleotides 1762 ( A - GT) and 1764 ( G - A) in the core promoter region were found in the majority of cases, mutations that have previously been reported in HBV that is integrated in HCC DNA. In serologic surveys to determine etiologic associations of HCC, patients such as those in this study would have been incorrectly designated as having 'HCV- associated HCC,' whereas the data in this study suggest that HBV could have played a role in the development of their HCCs.