慢性乙型肝炎进展期肝纤维化患者病毒基因型与肝细胞癌发生风险的相关性分析
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摘要
目的探讨慢性乙型肝炎(CHB)进展期肝纤维化患者病毒基因型与肝细胞癌发生风险的相关性。方法选取诊治的CHB患者59例为CHB组,CHB进展期肝纤维化患者62例为肝纤维化组,69例肝细胞癌患者为肝细胞癌组。观察3组患者血清学指标与病毒学指标[血清丙氨酸氨基转移酶(ALT)、白蛋白(Alb)、乙型肝炎病毒(HBV)DNA载量、透明质酸(HA)、甲胎蛋白(AFP)、乙型肝炎病毒e抗原(HBeAg)阳性率]。采用多重PCR扩增检测HBV基因型,并采用PCR扩增结合限制性片段长度多态性(RFLP)方法检测基因亚型。收集肝细胞癌患者的临床病理特征资料并观察HBV基因型与临床指标的关系。Logistic多元回归分析影响肝细胞癌发生的危险因素。结果 HBV B基因型在肝纤维化组与肝细胞癌组的比例显著低于CHB组(P<0.05),且肝细胞癌组显著低于肝纤维化组(P<0.05);HBV C基因型在肝纤维化组与肝细胞癌组的比例显著高于CHB组(P<0.05),且肝细胞癌组显著高于肝纤维化组(P<0.05);肝纤维化组HBV C2基因型患者血清ALT与HA水平均显著高于B2型(P<0.05),肝细胞癌组HBV C2基因型患者血清ALT、Alb、HA、AFP水平及HBeAg阳性率均显著高于B2型(P<0.05),且肝细胞癌组HBV C2基因型患者血清ALT、HA、AFP水平显著高于肝纤维化组(P<0.05);肝细胞癌HBV B2/C2基因亚型与肿瘤大小明显相关(P<0.05),C2亚型与肝细胞癌伴肝纤维化及淋巴结转移明显相关(P<0.05);Logistic多元回归分析结果显示HBV基因型为CHB进展期肝纤维化患者发展为肝细胞癌的危险因素。结论 CHB进展期肝纤维化患者HBV基因型主要以B2与C2基因亚型为主,C2基因亚型与肝细胞癌发生有关。
Objective To investigate the correlation between the viral genotype in chronic hepatitis B(CHB) patients with progressive stage hepatic fibrosis and risk of hepatocellular carcinoma occurrence.Methods A total of 59 patients with CHB who were diagnosed and treated in our hospital were enrolled as CHB group, and the other 62 CHB patients with progressive stage hepatic fibrosis were enrolled as liver fibrosis group, and the 69 patients with hepatocellular carcinoma were enrolled as hepatocellular carcinoma group. The serological indexes and virology indexes including serum alanine transaminase(ALT), albumin(Alb), hepatitis B virus(HBV) DNA loading capacity, hyaluronic acid(HA), alpha fetoprotein(AFP), and hepatitis B virus e antigen(HBeAg) positive rate were observed and compared among the three groups. Moreover the HBV genotypes were detected by multiple PCR amplification, and the gene subtypes were detected by PCR amplification combined with restriction fragment length polymorphism(RFLP) mehod. The clinicopathological datum of patients with hepatocellular carcinoma were collected, and the relationship between HBV genotype and clinical indicators was analyzed.In addition the risk factors affecting the occurrence of hepatocellular carcinoma were analysed by Logistic multiple regression analysis.Results The proportion of HBV B genotype in liver fibrosis group and hepatocellular carcinoma group was significantly lower than that in CHB group(P<0.05), moreover the proportion of HBV B genotype in hepatocellular carcinoma group was significantly lower than that in liver fibrosis group(P<0.05). The proportion of HBV C genotype in liver fibrosis group and hepatocellular carcinoma group was significantly higher than that in CHB group(P<0.05), which in hepatocellular carcinoma group was significantly higher than that in liver fibrosis group(P<0.05). The serum levels of ALT and HA in patients with HBV C2 genotype in liver fibrosis group were significantly higher than those of patients with HBV B2 genotype(P<0.05), however the serum levels of ALT, Alb, HA, AFP and the positive rate of HBeAg in patients with HBV C2 genotype in hepatocellular carcinoma group were significantly higher than those in patients with HBV B2 genotype(P<0. 05),moreovr the serum levels of ALT,HA and AFP in patients with HBV C2 genotype in hepatocellular carcinoma group were significantly higher than those in liver fibrosis group( P < 0. 05). The HBV B2/C2 gene subtype in hepatocellular carcinoma was closely correlated with tumor size( P < 0. 05),moreover the C2 subtype was significantly correlated with hepatocellular carcinoma combinedhepatic fibrosis and lymph node metastasis( P< 0. 05). The results of Logistic multiple regression analysis showed that HBV genotype was a risk factor for CHB patients with liver fibrosis in progressive stage to develop hepatocellular carcinoma. Conclusion HBV genotype in CHB patients with liver fibrosis in progressive stage is mainly B2 and C2 gene subtypes,and C2 gene subtype is correlated with hepatocellular carcinoma pathogenesis.
Objective To investigate the correlation between the viral genotype in chronic hepatitis B(CHB) patients with progressive stage hepatic fibrosis and risk of hepatocellular carcinoma occurrence.Methods A total of 59 patients with CHB who were diagnosed and treated in our hospital were enrolled as CHB group, and the other 62 CHB patients with progressive stage hepatic fibrosis were enrolled as liver fibrosis group, and the 69 patients with hepatocellular carcinoma were enrolled as hepatocellular carcinoma group. The serological indexes and virology indexes including serum alanine transaminase(ALT), albumin(Alb), hepatitis B virus(HBV) DNA loading capacity, hyaluronic acid(HA), alpha fetoprotein(AFP), and hepatitis B virus e antigen(HBeAg) positive rate were observed and compared among the three groups. Moreover the HBV genotypes were detected by multiple PCR amplification, and the gene subtypes were detected by PCR amplification combined with restriction fragment length polymorphism(RFLP) mehod. The clinicopathological datum of patients with hepatocellular carcinoma were collected, and the relationship between HBV genotype and clinical indicators was analyzed.In addition the risk factors affecting the occurrence of hepatocellular carcinoma were analysed by Logistic multiple regression analysis.Results The proportion of HBV B genotype in liver fibrosis group and hepatocellular carcinoma group was significantly lower than that in CHB group(P<0.05), moreover the proportion of HBV B genotype in hepatocellular carcinoma group was significantly lower than that in liver fibrosis group(P<0.05). The proportion of HBV C genotype in liver fibrosis group and hepatocellular carcinoma group was significantly higher than that in CHB group(P<0.05), which in hepatocellular carcinoma group was significantly higher than that in liver fibrosis group(P<0.05). The serum levels of ALT and HA in patients with HBV C2 genotype in liver fibrosis group were significantly higher than those of patients with HBV B2 genotype(P<0.05), however the serum levels of ALT, Alb, HA, AFP and the positive rate of HBeAg in patients with HBV C2 genotype in hepatocellular carcinoma group were significantly higher than those in patients with HBV B2 genotype(P<0. 05),moreovr the serum levels of ALT,HA and AFP in patients with HBV C2 genotype in hepatocellular carcinoma group were significantly higher than those in liver fibrosis group( P < 0. 05). The HBV B2/C2 gene subtype in hepatocellular carcinoma was closely correlated with tumor size( P < 0. 05),moreover the C2 subtype was significantly correlated with hepatocellular carcinoma combinedhepatic fibrosis and lymph node metastasis( P< 0. 05). The results of Logistic multiple regression analysis showed that HBV genotype was a risk factor for CHB patients with liver fibrosis in progressive stage to develop hepatocellular carcinoma. Conclusion HBV genotype in CHB patients with liver fibrosis in progressive stage is mainly B2 and C2 gene subtypes,and C2 gene subtype is correlated with hepatocellular carcinoma pathogenesis.
引文
1 Saikia A,Bose M,Barman NM,et al.Molecular epidemiology of HBV infection in chronic hepatitis B virus infected patients in northeast India.J Med Virol,2015,87:1539-1548.
2 丁红方,马科,宁琴.Fibroscan无创检测慢性乙型肝炎病毒携带者肝纤维化的临床意义.华中科技大学学报(医学版),2015,44:572-574.
3 Rajbhandari R,Danford CJ,Chung RT,et al.HBV infection is associated with greater mortality in hospitalised patients compared to HCV infection or alcoholic liver disease.Aliment Pharmacol Ther,2015,41:928-938.
4 曾华,张智贤,梁倩文,等.乙型肝炎病毒B、C基因型与临床表现.广州医科大学学报,2015,43:58-60.
5 常丽娜,王金萍,施卫兵,等.超声引导下肝组织活检术在轻度慢性乙型肝炎诊断中的作用.安徽医药,2013,17:51-52.
6 陆伟,张占卿,沈芳,等.血清HBsAg和HBV DNA定量水平预测慢性乙型肝炎患者肝组织炎症活动度和纤维化程度的评价.实用肝脏病杂志,2016,19:20-25.
7 陆玉敏,吴英宇,李振宇,等.肝细胞癌CT表现、肝外转移与病理分级和P53蛋白表达的关系.临床放射学杂志,2014,33:1680-16836.
8 罗懿忠,区金锐.TNM分期评价肝癌术后TACE及预后的价值.广东医学,2009,30:1701-1703.
9 中华医学会肝病学分会.慢性乙型肝炎防治指南(2010年版).中华内科杂志,2011,3:1-12.
10 Tanaka Y,Orito E,Yuen ME,et al.Two subtypes(subgenotypes) of hepatitis B virus genotype C:a novel subtyping assay based on restriction fragment length polymorphism.Hepatol Res,2005,33:216-224.
11 欧晓娟,王晓明,吴晓宁,等.FibroTouch与FibroScan在慢性乙型肝炎患者肝纤维化评估中的比较.中华肝脏病杂志,2015,23:103- 106.
12 Coppola N,Onorato L,Panella M,et al.Correlation between the hepatic expression of human microRNA hsa-miR-125a-5p and the progression of fibrosis in patients with overt and occult HBV infection.Front Immunol,2018,9:1334.
13 Li C,Bi X,Huang Y,et al.Variants identified by hepatocellular carcinoma and chronic hepatitis B virus infection susceptibility GWAS associated with survival in HBV-related hepatocellular carcinoma.PLoS One,2014,9:e101586.
14 江杰,黄新颜,王利红,等.HBV感染者病毒基因型分布特点及其与干扰素疗效的关系.实用肝脏病杂志,2014,17:299-300.
15 Baatarkhuu O,Gerelchimeg T,Munkh-Orshikh D,et al.Epidemiology,genotype distribution,prognosis,control,and management of viral hepatitis B,C,D,and hepatocellular carcinoma in mongolia.Euroasian J Hepatogastroenterol,2018,8:57-62.
16 Ormeci A,Aydin Y,Sumnu A,et al.Predictors of treatment requirement in HBeAg-negative chronic hepatitis B patients with persistently normal alanine aminotransferase and high serum HBV DNA levels.Int J Infect Dis,2016,52:68-73.
17 Yang G,Han M,Chen F,et al.Hepatitis B virus genotype B and mutations in basal core promoter and pre-core/core genes associated with acute-on-chronic liver failure:a multicenter cross-sectional study in China.Hepatol Int,2014,8:508-516.
18 陈洁,张欣欣.乙型肝炎病毒特征与肝硬化及原发性肝细胞癌关系的研究进展.中华肝脏病杂志,2014,22:153-155.
19 雷蔓,何松.慢性乙型肝炎、乙型肝炎肝硬化及原发性肝癌患者HBV-X基因突变分析.临床肝胆病杂志,2014,30:531-536.
2 丁红方,马科,宁琴.Fibroscan无创检测慢性乙型肝炎病毒携带者肝纤维化的临床意义.华中科技大学学报(医学版),2015,44:572-574.
3 Rajbhandari R,Danford CJ,Chung RT,et al.HBV infection is associated with greater mortality in hospitalised patients compared to HCV infection or alcoholic liver disease.Aliment Pharmacol Ther,2015,41:928-938.
4 曾华,张智贤,梁倩文,等.乙型肝炎病毒B、C基因型与临床表现.广州医科大学学报,2015,43:58-60.
5 常丽娜,王金萍,施卫兵,等.超声引导下肝组织活检术在轻度慢性乙型肝炎诊断中的作用.安徽医药,2013,17:51-52.
6 陆伟,张占卿,沈芳,等.血清HBsAg和HBV DNA定量水平预测慢性乙型肝炎患者肝组织炎症活动度和纤维化程度的评价.实用肝脏病杂志,2016,19:20-25.
7 陆玉敏,吴英宇,李振宇,等.肝细胞癌CT表现、肝外转移与病理分级和P53蛋白表达的关系.临床放射学杂志,2014,33:1680-16836.
8 罗懿忠,区金锐.TNM分期评价肝癌术后TACE及预后的价值.广东医学,2009,30:1701-1703.
9 中华医学会肝病学分会.慢性乙型肝炎防治指南(2010年版).中华内科杂志,2011,3:1-12.
10 Tanaka Y,Orito E,Yuen ME,et al.Two subtypes(subgenotypes) of hepatitis B virus genotype C:a novel subtyping assay based on restriction fragment length polymorphism.Hepatol Res,2005,33:216-224.
11 欧晓娟,王晓明,吴晓宁,等.FibroTouch与FibroScan在慢性乙型肝炎患者肝纤维化评估中的比较.中华肝脏病杂志,2015,23:103- 106.
12 Coppola N,Onorato L,Panella M,et al.Correlation between the hepatic expression of human microRNA hsa-miR-125a-5p and the progression of fibrosis in patients with overt and occult HBV infection.Front Immunol,2018,9:1334.
13 Li C,Bi X,Huang Y,et al.Variants identified by hepatocellular carcinoma and chronic hepatitis B virus infection susceptibility GWAS associated with survival in HBV-related hepatocellular carcinoma.PLoS One,2014,9:e101586.
14 江杰,黄新颜,王利红,等.HBV感染者病毒基因型分布特点及其与干扰素疗效的关系.实用肝脏病杂志,2014,17:299-300.
15 Baatarkhuu O,Gerelchimeg T,Munkh-Orshikh D,et al.Epidemiology,genotype distribution,prognosis,control,and management of viral hepatitis B,C,D,and hepatocellular carcinoma in mongolia.Euroasian J Hepatogastroenterol,2018,8:57-62.
16 Ormeci A,Aydin Y,Sumnu A,et al.Predictors of treatment requirement in HBeAg-negative chronic hepatitis B patients with persistently normal alanine aminotransferase and high serum HBV DNA levels.Int J Infect Dis,2016,52:68-73.
17 Yang G,Han M,Chen F,et al.Hepatitis B virus genotype B and mutations in basal core promoter and pre-core/core genes associated with acute-on-chronic liver failure:a multicenter cross-sectional study in China.Hepatol Int,2014,8:508-516.
18 陈洁,张欣欣.乙型肝炎病毒特征与肝硬化及原发性肝细胞癌关系的研究进展.中华肝脏病杂志,2014,22:153-155.
19 雷蔓,何松.慢性乙型肝炎、乙型肝炎肝硬化及原发性肝癌患者HBV-X基因突变分析.临床肝胆病杂志,2014,30:531-536.