在未检测到乙型肝炎表面抗原和肝细胞癌的患者中，高比例

StephenW

Among Patients with Undetectable Hepatitis B Surface Antigen and Hepatocellular Carcinoma, a High Proportion Has Integration of HBV DNA into Hepatocyte DNA and No Cirrhosis
Danny Ka-Ho Wong1,2
, Serene Ching Yan Cheng1
, Loey Lung-Yi Mak1
, Elvis Wai-Pan To1
, Regina Cheuk-Lam Lo2,3
, Tan-To Cheung2,4
, Wai-Kay Seto1,2
, James Fung1,2
, Kwan Man2,4
, Ching-Lung Lai1,2
, Man-Fung Yuen1,2,∗,'Correspondence information about the author Man-Fung YuenEmail the author Man-Fung Yuen
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    Abstract

Abstract
Background & Aims

In some individuals with undetectable serum levels of hepatitis B surface antigen (HBsAg), hepatitis B virus (HBV) DNA can still be detected in serum or hepatocytes and HBV replicates at low levels—this is called occult HBV infection (OBI). OBI has been associated with increased risk of hepatocellular carcinoma (HCC). We investigated the incidence of OBI in patients with HCC and other liver diseases. We also investigated whether, in patients with OBI and HCC, HBV DNA has integrated into the DNA of hepatocytes.
Methods

We collected clinical information and liver tissues from 110 HBsAg-negative patients (90 with HCC and 20 without HCC; median ages at surgical resection and biopsy collection, 64.1 and 48.6 years, respectively) who underwent liver resection or liver biopsy from November 2002 through July 2017 in Hong Kong. HBV DNA and covalently closed circular DNA (cccDNA) were analyzed and quantified by PCR in liver tissues. Integration of HBV DNA into the DNA of liver cells was detected by Alu-PCR.
Results

Of the 90 HBsAg-negative patients with HCC, 18 had alcoholic liver disease (20%), 14 had non-alcoholic fatty liver disease or steatohepatitis (16%), 2 had primary biliary cholangitis, 2 had recurrent pyogenic cholangitis, 1 had autoimmune hepatitis, and 53 had none of these (59%). Among the 20 patients without HCC, 7 had non-alcoholic fatty liver disease or steatohepatitis, 7 had primary biliary cholangitis, and 6 had autoimmune hepatitis. OBI was detected in 62/90 patients with HCC (69%) and 3/20 patients without HCC (15%) (P<.0001). cccDNA was detectable in liver cells of 29 patients with HCC and OBI (47%) and HBV DNA had integrated into DNA of liver cells of 43 patients with HCC and OBI (69%); cccDNA and integrated HBV DNA were not detected in the 3 patients who had OBI without HCC. There were 29 patients with integration of HBV DNA among 33 patients with undetectable cccDNA in liver tissues (88%) and 14 patients with integration of HBV DNA among the 29 patients with cccDNA in liver tissues (48%) (P=.001). HBV DNA was found to integrate near genes associated with hepatocarcinogenesis, such as those encoding telomerase reverse transcriptase, lysine methyltransferase 2B, and cyclin A2. Among the 43 patients with integration of HBV DNA, 39 (91%) did not have cirrhosis.
Conclusions

In an analysis of clinical data and liver tissues from 90 HBsAg-negative patients with HCC, we found that almost 70% had OBI, of whom 70% had integration of HBV DNA into liver cell DNA; 90% of these patients did not have cirrhosis. HBV DNA integrated near hepatic oncogenes; these integrations might promote development of liver cancer.
Key Words:
non-viral liver disease, tumorigenesis, NAFLD, NASH
Abbreviations used in this paper:
CHB (chronic hepatitis B), HCC (hepatocellular carcinoma), CHC (chronic hepatitis C), ALD (alcoholic liver disease), NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic steatohepatitis), AIH (autoimmune hepatitis), PBC (primary biliary cholangitis), RPC (recurrent pyogenic cholangitis), HBV (hepatitis B virus), OBI (occult HBV infection), HBsAg (hepatitis B surface antigen), HCV (hepatitis C virus), anti-HBc (antibodies-to-hepatitis B core antigen), cccDNA (covalently closed circular DNA)

StephenW

在未检测到乙型肝炎表面抗原和肝细胞癌的患者中，高比例的HBV DNA被整合到肝细胞DNA中并且没有肝硬化
Danny Ka-Ho Wong1,2
，Serene Ching Yan Cheng1
，Loey Lung-Yi Mak1
，Elvis Wai-Pan To1
，Regina Cheuk-Lam Lo2,3
，Tan-To Cheung2,4
，Wai-Kay Seto1,2
，James Fung1,2
，Kwan Man2,4
，Ching-Lung Lai1,2
，Man-Fung Yuen1,2，*，'关于作者的沟通信息Man-Fung Yuen电子书作者Man-Fung Yuen
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抽象

抽象
背景和目的

在未检测到血清乙型肝炎表面抗原（HBsAg）水平的个体中，仍可在血清或肝细胞中检测到乙型肝炎病毒（HBV）DNA，并且HBV复制水平较低 - 这称为隐匿性HBV。感染（OBI）。 OBI与肝细胞癌（HCC）风险增加有关。我们调查了HCC和其他肝脏疾病患者的OBI发生率。我们还研究了HBI DNA是否已经整合到OBI和HCC患者的肝细胞DNA中。
方法

我们收集了2002年11月至7月接受肝切除术或肝活检的110例HBsAg阴性患者（90例HCC，20例无HCC，手术切除和活检中位年龄，64.1和48.6岁）的临床资料。 2017.HBV DNA和共价闭合环状DNA（cccDNA）在肝组织中通过PCR进行分析和定量。通过Alu-PCR检测HBV DNA整合到肝细胞DNA中。
结果

在90例HBsAg阴性的HCC患者中，18例患有酒精性肝病（20％），14例患有非酒精性脂肪性肝病或脂肪性肝炎（16％），2例患有原发性胆源。性胆管炎，2例复发性化脓性胆管炎，1例自身免疫性疾病。肝炎，53人没有（59％）。在没有HCC的20名患者中，7名患有非酒精性脂肪性肝病或脂肪性肝炎，7名患有原发性胆汁性胆管炎，6名患有自身免疫性肝炎。在62/90例HCC患者（69％）和3/20例无HCC患者（15％）中检测到OBI（P <.0001）。在29例HCC和OBI患者的肝细胞中检测到cccDNA（47％），并将HBV DNA整合到43例HCC和OBI患者的肝细胞DNA中（69％）;在没有HCC的3名OBI患者中未检测到cccDNA和整合的HBV DNA。在33例肝组织患者中，29例HBV DNA整合（88％），29例肝cccDNA患者中有29例HBV DNA整合（48％）（P = .001）。发现HBV DNA整合了与肝癌发展相关的基因，如编码端粒酶逆转录酶，赖氨酸甲基转移酶2B和细胞周期蛋白A2的基因。在43例HBV DNA整合患者中，39例（91％）没有肝硬化。
结论

在对90例HBsAg阴性HCC患者的临床资料和肝组织进行分析时，我们发现近70％的人患有OBI，其中70％的人将HBV DNA整合到肝细胞DNA中;这些患者中有90％％没有肝硬化。 HBV DNA整合在肝癌基因附近;这些整合可能会促进肝癌的发展。
关键词：
非病毒性肝病，肿瘤发生，NAFLD，NASH
本文中使用的缩写：
CHB（慢性乙型肝炎），HCC（肝细胞癌），CHC（慢性丙型肝炎），ALD（酒精性肝病），NAFLD（非酒精性脂肪性肝病），NASH（非酒精性脂肪性肝炎），AIH（自身免疫性肝炎），PBC（原发性肝炎）胆汁性胆管炎），RPC（复发性化脓性胆管炎），HBV（乙型肝炎病毒），OBI（隐匿性HBV感染），HBsAg（乙型肝炎）表面抗原），HCV（丙型肝炎病毒），抗HBc（抗肝炎抗体） B核心抗原），cccDNA（共价闭合环状DNA）