隐匿性乙型肝炎病毒感染

大量研究通过对肝组织和血清乙型肝炎病毒（HBV）DNA或转录体的检测，证实隐匿性HBV感染是所谓“隐源性肝炎”及其它慢性肝病的常见病因。现就其发生率、形成机制、临床意义、诊断、治疗等方面作一综述。     

无偿献血人群隐匿性乙型肝炎病毒感染调查

目的 调查无偿献血人群隐匿性乙型肝炎病毒感染(OBI)情况。方法 2021年1月～2021年12月我站无偿献血者血液样本107397份,采用两种ELISA法检测试剂盒进行HBsAg的初次筛查,采用核酸检测(NAT)法对两次HBsAg结果均为阴性的样本进行HBV DNA检测。对血清HBsAg阴性而HBV DNA阳性样本进行HBV血清学标志物检测,并采用实时荧光定量聚合酶链式反应(PCR)法检测核酸和病毒基因分型。结果 在筛查的107397例无偿献血人群血样本中,经血清标志物检测后确认为OBI者29例(0.27‰);血清抗-HBc阳性者12例(35.3%),抗-HBe/抗-HBc阳性者8例(23.5%),抗-HBs/抗-HBc阳性者6例(17.7%),抗-HBs/抗-HBe/抗-HBc阳性者3例(8.8%);19～29岁年龄段献血人群OBI感染率为0.09‰,30～39岁人群为0.32‰,40～49岁人群为0.39‰,50～55岁年龄段献血人群OBI感染率为0.41‰,且该年龄段重复献血者OBI感染率为0.31‰;血清抗-HBs/抗-HBc阳性和抗-HBs/抗-HBe/抗-HBc OBI献...     

隐匿性乙型肝炎病毒感染的研究进展

隐匿性乙型肝炎病毒感染(occult HBV infection, OBI)是公共健康的一大难题,也是全球临床医学面临的挑战。由于目前检测方法以及临床实际问题的限制,不同研究中对于OBI的定义也不同。OBI的存在会影响临床诊断和输血安全,且OBI在临床高危人群中有再激活的风险,可能会导致肝硬化、肝癌和肝衰竭等终末期肝病。本文就近年OBI定义和不同人群流行率、OBI发生机制以及临床意义等研究进展进行综述。     

HBsAb阳性隐匿性HBV感染者血清、肝组织HBV全基因序列分析

目的 了解HBsAb阳性隐匿性HBV感染者血清和肝组织中的HBV基因序列,并比较其差异性.方法 以1例长期随访HBsAb阳性隐匿性HBV感染者作为研究对象,用多种试剂盒检测其血清HBsAg、HBsAb,提取外周血血清和肝组织HBV DNA进行全基因组分段扩增,行序列测定及同源性比较.结果 多种试剂盒检测均提示该例患者HBsAg阴性、HBsAb阳性;血清HBV DNA为103～ 105拷贝/mL;血清和肝组织来源的HBV DNA全基因测序完全相同,均为3 215个碱基、B基因型,与参照序列核苷酸同源性为98.82％,各编码区均没有缺失或移码突变,不同编码区的核苷酸序列同源性为98.37％～ 100％,氨基酸序列同源性为98.18％～ 100％,在S区存在几种变异如PreS1的Q80H、S的C64Y、E164G、L175S,但前S区、“a”决定簇、1 762/1 764、1 896位点均未见变异.结论 HBsAb阳性隐匿性HBV感染者血清和肝组织来源的HBV基因序列无明显差异.     

隐匿性乙型肝炎病毒感染与输血安全

随着分子生物学技术的发展，特别是聚合酶链反应（PCR）检测灵敏度不断提高，近年来可发现部分HBsAg阴性人群血清中可检出低水平的HBV-DNA，这种复制水平较低的HBV感染状态可见于抗-HBs或抗-HBc阳性的患者，也可见于HBV血清标志物全阴的患者；在部分HBsAg阴转的急性或慢性乙肝患者的血清中仍可检测出低水平的HBV-DNA，     

隐匿性乙型肝炎病毒感染

隐匿性HBV感染可定义为病毒基因在HBsAg阴性个体的肝组织中（有些也存在于血清中）长期持续存在。这种特殊慢性病毒感染估计在上世纪80年代初就存在,然而在最近10年里才得到很好的认识。高灵敏分子生物学技术的出现使得认识这种感染病毒成为可能,并揭示其与许多临床疾病可能存在联系。     

隐匿性乙型肝炎病毒感染

随着分子生物学技术在病毒检测技术中的应用,近年来发现部分复制水平较低的乙型肝炎病毒携带者血清中检测不到HBV表面抗原（HBsAg）,这种感染状态可发生于抗-HBs或抗-HBc阳性的患者,也可见于HBV标志物全阴性的患者;部分HBsAg阴转的急性或慢性乙肝患者,其血清中仍可检测出低水平HBVDNA或肝组织中检测出HBsAg或HBcAg,这种患者被称为HBV隐匿感染。     

隐匿性乙型肝炎:免疫组织化学和S基因序列分析

目的　了解不明原因慢性肝病中隐匿性乙型肝炎所占比例 ,隐匿性乙型肝炎的发病机制及临床、病理特点。方法　给予 2 0例不明原因慢性肝病患者肝穿刺病理检查 ,应用免疫组织化学方法检测肝组织内的乙型肝炎病毒表面抗原 (HBsAg)、核心抗原 (HBcAg) ,丙型肝炎病毒NS3、NS4抗原。采用荧光定量PCR方法对血清HBVDNA进行定量 ,用套式PCR方法扩增HBVS基因 ,对PCR产物进行直接测序 ,比较S基因的核苷酸和推导出的氨基酸序列的差异。结果　 5例患者经肝脏病理检查表现为慢性炎症 ,3例在肝组织内HBsAg、HBcAg同时阳性 ,2例仅HBcAg阳性。S基因的氨基酸序列分析显示 ,1例患者S基因的 74位密码子发生终止变异 ,另 1例在HBsAg的“a”决定簇内有 2个氨基酸发生变异 (T13 1N ,M 13 3S) ,其他 3例患者HBsAg的“a”决定簇内未发现变异。 结论　在我国隐匿性乙型肝炎是不明原因肝病的主要原因之一 ,低水平的血清HBVDNA可以引起慢性肝炎。部分隐匿性乙型肝炎HBsAg阴性的原因是S基因变异引起的 ,而有些患者则可能因为血清HBsAg水平过低 ,导致HBsAg检测阴性。     

乙型肝炎病毒感染模型的研究进展

HBV感染是影响人类健康的主要问题之一。HBV的生物学研究及治疗方法进展缓慢是由于缺乏合适的体内外模型。如何建立一种有效的HBV感染模型，对于探索其感染机制，寻找有效的防治方法及开展抗HBV药物的筛选都具有重要的科研及临床意义。随着医学科学的不断发展，国内外学者进行了大量的研究，建立了多种HBV感染的体内外模型，每一种模型都有其优势和弊端，本文简要综述了各种模型存HBV研究中的应用进展及相应优、缺点。     

隐匿性乙型肝炎病毒感染

隐匿性HBV感染是指血清HBsAg阴性,而应用聚合酶链反应（PCR）技术检测血清和（或）肝组织中HBVDNA阳性。可以分为两类,一类是可检出血清HBV标志,包括抗一HBs阳性、抗-HBc阳性或抗-HBe阳性;另一类是所有HBV标志均阴性。隐匿性HBV感染作为乙型肝炎病毒感染的一种特殊类型,是临床和流行病学的一大难题。     

Occult hepatitis B virus infection and its clinical implications

Occult hepatitis B virus (HBV) infection is characterized by presence of HBV infection with undetectable hepatitis B surface antigen (HBsAg). Serum HBV level is usually less than 10⁴ copies/mL in these patients. Diagnosis of occult HBV infection requires sensitive HBV-DNA PCR assay. Several possibilities have been hypothesized as the mechanisms of occult HBV infection. These include: (i) mutations of HBV-DNA sequence; (ii) integration of HBV-DNA into host's chromosomes; (iii) infection of peripheral blood mononuclear cells by HBV; (iv) formation of HBV-containing immune complex; (v) altered host immune response; and (vi) interference of HBV by other viruses. The precise prevalence of occult HBV infection remains to be defined. The clinical implications of occult HBV infection involve different clinical aspects. First of all, occult HBV infection harbours potential risk of HBV transmission through blood transfusion, haemodialysis, and organ transplantation. Second, it may serve as the cause of cryptogenic liver disease, contribute to acute exacerbation of chronic hepatitis B, or even fulminant hepatitis. Third, it is associated with development of hepatocellular carcinoma. Fourth, it may affect disease progression and treatment response of chronic hepatitis C. Most of the previous studies utilized retrospective observation without control groups, and lacked direct association of occult HBV infection with specific pathological changes and disease progression. Highly sensitive, quantitative, and functional molecular analyses of HBV, combined with a well-designed prospective clinical assessment will provide the best approach for the future study of occult HBV infection.     

Novel hepatitis B virus surface antigen mutations associated with occult genotype B hepatitis B virus infection affect HBsAg detection

The causative factors of occult hepatitis B infection are complicated and not yet been fully elucidated. Mutations in hepatitis B virus (HBV) S gene are one of the factors may contributing to occult infection. In this study, 89 blood donors with genotype B occult HBV infection were investigated. Fifty‐seven hepatitis B surface antigen (HBsAg)‐positive/HBV DNA‐positive blood donors served as control group for comparison. Occult HBV‐related mutations with a high incidence (P < .05) in the S gene were identified. To further verify these occult infection‐related mutations, a conservative full‐gene expression vector of HBV B genotype (pHBV1.3B) was constructed. Then, the mutant plasmids on the basis of pHBV1.3B were constructed and transfected into HepG2 cells. Extracellular as well as intracellular HBsAg was analysed by electrochemical luminescence and cellular immunohistochemistry. Ten occult infection‐related mutations (E2G, Q101R, K122R, M133T, D144E, G145R, V168A, S174N, L175S and I226S) were significantly more frequent in the occult infection group (P < .05). Five of the ten mutations (E2G, D144E, G145R, V168A and S174N) strongly decreased extracellular HBsAg level (P < .05) in the transfection system. Notably, the E2G mutation had the most significant impact on the ratio of extracellular HBsAg (3.8% vs pHBV1.3B) and intracellular HBsAg (239.3% vs pHBV1.3B) (P < .05), and the fluorescence density of E2G mutant HBsAg was significantly higher than that of pHBV1.3B (P < .0001). Hence, ten mutations were associated with genotype B occult HBV infection; E2G and V168A were novel mutations which we confirmed significantly affect HBsAg detection. E2G might cause HBsAg secretion impairment that results in intracellular accumulation and a decrease in HBsAg secretion.     

Pathogenesis of occult chronic hepatitis B virus infection

Occult hepatitis B infection(OBI) is characterized by hepatitis B virus(HBV) DNA in serum in the absence of hepatitis B surface antigen(HBsAg) presenting HBsAg-negative and anti-HBc positive serological patterns.Occult HBV status is associated in some cases with mutant viruses undetectable by HBsAg assays;but more frequently it is due to a strong suppression of viral replication and gene expression.OBI is an entity with world-wide diffusion.The failure to detect HBsAg,despite the persistence of the viral DN...     

Persistent occult hepatitis B virus infection： Experimental findings and clinical implications

Hepatitis B virus （HBV） is a highly pathogenic virus that causes chronic liver diseases in millions of people globally. In addition to a symptomatic, serologically evident infection, occult persistent HBV carriage has been identified since nucleic acid amplification assays of enhanced sensitivity became introduced for detection of hepadnaviral genomes and their replicative intermediates. Current evidence indicates that occult HBV infection is a common and long-term consequence of resolution of acute hepatitis B. This form of residual infection is termed as secondary occult infection （SOI）. The data from the woodchuck model of HBV infection indicate that exposure to small amounts of hepadnavirus can also cause primary occult infection （POI） where virus genome, but no serological makers of exposure to virus, are detectable, and the liver may not be involved. However, virus replicates at low levels in the lymphatic system in both these forms. We briefly summarize the current understanding of the nature and characteristics of occult hepadnaviral persistence as well as of its documented and expected pathological consequences.     

Hepatitis B virus genotypes and hepatitis B surface antigen mutations in family contacts of hepatitis B virus infected patients with occult hepatitis B virus infection

Background:  The association and profile of surface gene mutations with viral genotypes have been studied in patients with chronic hepatitis B virus (HBV) but not in subjects with occult HBV infection.
Aim:  This study aimed to investigate the association of surface gene mutations with viral genotypes in occult HBV infection.
Materials & Methods:  Of 293 family contacts of 90 chronic HBV index patients, 110 consented for the study. Of 110 subjects, 97 were hepatitis B surface antigen (HBsAg) negative. HBV genotyping was done using direct DNA sequencing. The S-gene was also sequenced in 13 chronic hepatitis B patients to serve as controls.
Results:  Twenty-eight (28.8%) of the 97 subjects had occult HBV infection. Bidirectional sequencing of partial S-gene was successful in 13 of them. Seven (53.8%) of the viral sequences are genotype A1, two (15.3%) each having genotypes D5&D2 and one each (7.6%) having D1&G genotypes. Seven (53.8%) of the 13 HBsAg positive patients, had genotype D&6 (46.1%) genotype A. A128V & T143M mutations were observed in 5 of 13 (38.4%) subjects and A128V & P127S in 2 of 13 (15.3%) patients ( P  = 0.385). A128V mutation was seen in two (15.3%) subjects with D2 genotype, while T143M mutation was seen in three (23.07%) subjects with A1genotype. At aa125, three (23.07%) subjects with D5 genotype had methionine instead of threonine. There were wild type sequences in five (38.4%) subjects, one each of D1, G genotypes (20%) and four A1 (80%) genotypes. None of the subjects had G145R mutation.
Conclusions:  Occult HBV infection may be common in household contacts of chronic HBV infected patients. Equal prevalence of A&D sub-genotypes was present in occult HBV subjects and in chronic HBV patients. Mutations of the S-gene are genotype specific in both occult as well as chronic HBV infection.     

Long-term clinical impact of occult hepatitis B virus infection in chronic hepatitis B patients

BACKGROUND/AIMS: Long-term clinical outcomes of occult hepatitis B virus (HBV) infection were studied. METHODS: Fifteen chronic hepatitis B patients were monitored for a median of 4.4 years (range 0.9-15.3) after hepatitis B surface antigen (HBsAg) seroclearance. Serum HBV DNA was measured by real-time detection polymerase chain reaction. Thirteen patients underwent liver biopsies at the end of follow-up and liver histology was evaluated by Ishak score. Liver HBV DNA was also measured for 12 patients. RESULTS: At the end of follow-up, HBV viremia was absent in 13 (87%) patients, and antibody titers to hepatitis B core antigen showed an inverse correlation with time from HBsAg seroclearance (r=-0.554; P=0.0040). However, all patients retained liver HBV DNA and tested positive for the covalently closed circular HBV DNA replicative intermediate. The hepatic HBV DNA loads had no relation to liver histology. Paired biopsies from 11 patients disclosed that each necroinflammatory score significantly improved after HBsAg seroclearance. Amelioration of liver fibrosis was also evident in eight (73%) patients (P=0.0391 by signed rank test). CONCLUSIONS: A long-standing but strongly suppressed HBV infection may confer histological amelioration after HBsAg seroclearance.     

Overt and occult hepatitis B virus infection among community children in Northwest China

Although a universal newborn hepatitis B (HB) immunization programme has been implemented in China, hepatitis B virus (HBV) breakthrough infection, including HB surface antigen (HBsAg)‐positive infection and occult HBV infection (OBI), still occurs during infancy or childhood. Obtaining the actual prevalence of HBV infection in general children is important for preventing and controlling the spread of HB. Accordingly, we investigated the prevalence of overt infection and OBI in community children and compared the serological and virological characteristics of OBI and HBsAg carrier children to clarify the mechanisms related to OBI. In total, 6 706 community children <12 years of age were included from a population‐based HBV seroepidemiological investigation in Northwest China. The HBsAg carrier rate in community children was 1.60% (107/6706), and the anti‐HBs positive rate was 57.35% (3846/6706). Additionally, 1192 HBsAg‐negative children were examined for OBI using nested PCR. The prevalence of OBI in local children was 1.26% (15/1192), and the predominant OBI genotypes were C and D. The 15 OBI children and 29 HBsAg‐positive children from the same population did not have a statistical significant difference in age, gender, alanine aminotransferase (ALT), proportion of anti‐HBs or anti‐HBc, viral genotypes or mutations. Children with chronic overt infection had higher viral loads than OBI children (P=.004). These results suggested that HBV overt and occult infection of children was more serious in underdeveloped north‐west regions. HBV neonatal immunization and catch‐up programmes should be strengthened and supplemented. None of specific viral mutations or genotypes related to OBI were found. OBI may be a specific stage of HBV infection.     

Impact of occult hepatitis B virus infection and prior hepatitis B virus infection on development of hepatocellular carcinoma in patients with liver cirrhosis due to hepatitis C virus

Objective. Although hepatitis B virus (HBV) DNA can be detected in liver or sera of patients without serum hepatitis B surface antigen (HBsAg), its clinical relevance in hepatocarcinogenesis remains controversial. This observational cohort study was conducted to clarify the risk factors, including the presence of serum HBV DNA and hepatitis B core antibody (anti-HBc), for hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related liver cirrhosis (LC). Material and methods. The study comprised 123 patients with LC due to HCV, and negative for HBsAg. The risk factors for HCC development were analyzed by univariate and multivariate analysis. Serum samples were assayed for HBV DNA using real-time polymerase chain reaction. Results. Serum HBV DNA was detectable in 14 patients (11.4%) and serum anti-HBc in 96 (78.0%). During the follow-up period (mean 53.3 months), 80 patients (65.0%) developed HCC. The cumulative HCC development rate was significantly higher in the anti-HBc-positive group than in the anti-HBc-negative group (p=0.0039), but did not differ between the serum HBV DNA-positive and -negative groups (p=0.8570). The multivariate analysis indicated that male gender, alpha-fetoprotein (AFP) 20 ng/ml or greater, average serum alanine aminotransferase (ALAT) 80 IU/l or greater and the presence of anti-HBc were independent risk factors for development of HCC (p=0.038, p=0.013, p=0.020 and p=0.001, respectively). Conclusions. Serum anti-HBc, which indicates a previous HBV infection, has clinical significance in hepatocarcinogenesis in patients with HCV-related LC, but serum HBV DNA does not. Therefore, anti-HBc in serum is a significant predictor for HCC.     

Role of occult hepatitis B virus infection in chronic hepatitis C

The development of sensitive assays to detect small amounts of hepatitis B virus(HBV) DNA has favored the identification of occult hepatitis B infection(OBI), a virological condition characterized by a low level of HBV replication with detectable levels of HBV DNA in liver tissue but an absence of detectable surface antigen of HBV(HBs Ag) in serum. The gold standard to diagnose OBI is the detection of HBV DNA in the hepatocytes by highly sensitive and specific techniques, a diagnostic procedure requiring liver tissue to be tested and the use of non-standardized non-commercially available techniques. Consequently, in everyday clinical practice, the detection of anti-hepatitis B core antibody(antiHBc) in serum of HBs Ag-negative subjects is used as a surrogate marker to identify patients with OBI. In patients with chronic hepatitis C(CHC), OBI has been identified in nearly one-third of these cases. Considerable data suggest that OBI favors the increase of liver damage and the development of hepatocellular carcinoma(HCC) in patients with CHC. The data from other studies, however, indicate no influence of OBI on the natural history of CHC, particularly regarding the risk of developing HCC.