Landmark perspective: Landmarks in viral hepatitis

Developments in viral hepatitis have been traced from Saul Krugman's distinction of two types, MS1 and MS2 (A and B), and Baruch S. Blumberg's discovery of Australia antigen. Hepatitis A has been grown in tissue culture, the structure of the virus is known, and the acute disease can be diagnosed. Knowledge of the molecular biology of the more complex hepatitis B virion has allowed the development of an effective vaccine and distinction of replicative and nonreplicative stages of infection. Integration, in the hepatocyte, of hepatitis B viral DNA into host DNA is the precursor of liver cancer. The infection of hepatitis B carriers with another infectious agent, delta, has added a new dimension to the problem. Other unidentified causes of hepatitis have been lumped together as non-A, non-B, and these remain to be defined and accurately diagnosed.     

Relationship between hepatitis B virus DNA in blood and serological markers of hepatitis B infection

The hepatitis B virus (HBV) DNA dot-hybridization assay has been introduced into clinical practice in Australia and its behaviour compared with that of the classic markers of HBV infection. A good correlation exists between the presence of HBV DNA and that of hepatitis B e antigen but the degree of dissociation between HBV DNA and the e:anti-e system was smaller than earlier studies would suggest. Patients who are seronegative for hepatitis B surface antigen (HBsAg), whether they possess anti-HBs, anti-HBc HBc (antibody to the core antigen), or neither antibody, gave uniformly negative results for the presence of HBV DNA. Theses results are different from those that were obtained from earlier studies of patients with chronic liver disease.     

Transmission of hepatitis B virus by artificial insemination

Although the capacity for transmission of hepatitis B infection by semen is well recognized, the potential for transmission by artificial insemination remains theoretical. Currently, screening of semen donors for hepatitis B virus infection is not standard practice. We saw a case of acute viral hepatitis B in a woman following artificial insemination with semen from a donor subsequently found to be positive for hepatitis B surface antigen (HBsAg). Both the donor serum and semen contained HBsAg and hepatitis B e antigen, and the HBsAg subtype was identical to that of the patient. Documentation of hepatitis B virus transmission by artificial insemination indicates that HBsAg screening of semen donors should be routine practice.     

1783例乙型肝炎病毒血清学标志物检测结果分析

目的了解北海市中医院1783例患者接受乙型病毒性肝炎(HBV)两对半检测血清学标志物的特征,为HBV确诊治疗提供依据。方法采用酶联免疫吸附试验测定受检者血清中HBV表面抗原及抗体(HBsAg、HBsAb)、e抗原和抗体(HBeAg、HBeAb)以及核心抗体(HBcAb)。结果 HBsAg阳性总检出率为39.09%,男、女分别为46.94%和28.79%,差异有统计学意义(P<0.05)。受检者血清5项HBV病毒标志物表达模式有16种,以HBsAb阳性最多,占39.09%。结论血清病毒标志物表达模式反映了体内乙肝病毒感染情况,对检查HBsAb阴性的患者,建议疫苗接种进行预防。     

乙肝病毒PreS1抗原的临床应用

目的:评价检测乙肝病毒PreS1抗原的临床应用价值. 方法:将临床送检的1000份乙肝病毒表面抗原(HBsAg)阳性的血清标本进行PreS1抗原检测,同时用FQ-PCR进行HBV-DNA测定. 结果:PreS1总阳性率为52.0%,HBV-DNA阳性率为50.8%,HBeAg阳性率为21.0%. PreS1总阳性率明显高于HBeAg阳性率. PreS1与HBV-DNA的总符合率为94.4%. 结论:PreS1抗原作为乙肝感染和复制的血清学指标敏感性高于HBeAg,对提示乙肝患者的病情发展和转归有重要临床意义. PreS1可以作为一项新的乙肝病毒复制的传染性指标.     

乙型肝炎病毒核心启动子缺失变异对病毒抗原表达的影响

目的为研究乙型肝炎病毒(HBV)核心启动子(CP)20/21bp部分缺失(nt1748/1747至nt1767)及同时存在的A1896点变异对病毒抗原表达的影响。方法利用前期构建的HBV全基因的重组载体转染HepG2细胞后,对病毒抗原进行ELISA检测及Western-blotting分析。结果变异株分泌到细胞外的HBsAg、HBeAg及细胞内的HBcAg表达量较野毒株均明显减少。结论HBVCP20/21bp部分缺失株及同时存在的A1896点变异株的病毒抗原表达较野毒株显著下降。     

乙型肝炎疫苗免疫效果回顾性评价

目的：对从化市学龄前儿童乙型肝炎疫苗免疫效果进行回顾性分析,为我市制订乙型肝炎免疫策略提供参考数据。方法：通过对从化市1995～2005年学龄前儿童进行乙型肝炎感染的血清学检测,分析从化市学龄前儿童乙型肝炎病毒表面抗原（HBsAg）携带率,结合对从化市学龄前儿童乙型肝炎疫苗接种率等资料进行对比分析,并将当年该市农村学龄前幼儿HBsAg携带率进行比较,用以对从化市学龄前儿童乙型肝炎疫苗免疫效果进行回顾性评价。结果：随着乙型肝炎疫苗免疫接种率的逐年上升,从化市学龄前儿童乙型肝炎病毒表面抗原携带率则逐年下降,学龄前儿童HBsAg携带率由1995年的15.8%下降到2005年的4.5%（P〈0.05）。乙型肝炎保护性抗体（抗-HBs）则逐年上升,由1995年的39.9%升高到2005年的71.3%（P〈0.05）。同一时期内,城区学龄前儿童HBsAg携带率较农村儿童HBsAg携带率明显降低（P〈0.05）。结论：对学龄前儿童进行有组织有计划的乙型肝炎疫苗免疫接种,能够有效地降低学龄前儿童乙型肝炎病毒表面抗原（HBsAg）携带率;城区儿童乙型肝炎疫苗免疫接种率及接种效果均高于农村儿童。加强对乙肝易感人群的有计划的免疫,是降低乙肝感染的有效途径。     

Hepatitis B virus DNA and e antigen in serum from blood donors in the United Kingdom positive for hepatitis B surface antigen

Serum samples from 214 blood donors in the United Kingdom who were carriers of hepatitis B surface antigen (HBsAg) were examined for hepatitis B virus deoxyribonucleic acid (DNA) by DNA:DNA hybridisation and for hepatitis B e antigen (HBeAg) and its antibody. One fifth of the donors carried infectious virus in their circulation. The presence of hepatitis B virus DNA correlated well with that of HBeAg, although hepatitis B virus DNA was found in five serum samples that were negative for HBeAg. It is concluded that analysis of serum samples for hepatitis B virus DNA by hybridisation should be the method of choice for determining whether carriers of HBsAg are infectious.     

A study of hepatitis B virus DNA in situ hybridization for chronic active hepatitis.

Liver biopsies of 50 patients with chronic active hepatitis B were analysed immunohistochemically for HBcAg and HBsAg, and, by in situ hybridization, for hepatitis B virus (HBV) DNA. Double staining for manifesting HBV DNA and viral antigen simultaneously was also performed in some of them. The localization patterns of HBV DNA in hepatocytes could be classified into whole cytoplasmic, submembranous, nucleic and intermembranous types. The last type suggests that HBV DNA might be transmitted directly to the adjacent hepatocytes through the cell membranes. The double staining indicated that the majority of hepatocytes with high levels of HBV replication did not contain HBcAg of HBsAg. Conversely, most liver cells with strongly positive HBAg had low or negligible levels of viral replication. In addition, in a few cases HBV DNA could be found in the cytoplasm of bile ductule epithelia and sinusoidal endothelia.

     

乙型肝炎病毒核心启动子缺失变异对病毒抗原表达的影响

目的：为研究乙型肝炎病毒（HBV）核心启动子（CP）20／21bp部分缺失（nt1748/1747至nt1767)及同时存在的A1896点变异对病毒抗原表达的影响。方法：利用前期构建的HBV全基因的重组载体转染HepG2细胞后,对病毒抗原进行ELISA检测及Western-blotting分析。结果：变异株分泌到细胞外的HBsAg,HBeAg及细胞内的HBcAg表达量较野毒株均明显减少。结论：HBV CP20／21bp部分缺失株及同时存在的A1896点变异株的病毒抗原表达较野毒株显著下降。     

HBsAg/HBsAb double positive hepatitis B virus infection model <Emphasis Type="Italic">in vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis>

The pathogenesis of HBsAg （＋）/HBsAb （＋） double positive hepatitis B virus infection was investigated by simulating HBsAg/HBsAb coexistence in vitro and establishing HBsAg/HBsAb double positive model in vivo. Eukaryotic expression plasmids PCI-SY, PCI-adw, PCI-adr, PCI-ayw, which expressed S gene product of different serotypes, were constructed and transfected into HepG2 cells. Recombinant proteins were purified from the transfected cells. At the same time, HBsAg mouse antiserum was obtained by immunizing mice with PCI-SY plasmid. HBsAg/HBsAb coexistence was simulated using these antigens and antiserum. Furthermore, the expression plasmids expressing different serotypes of S gene product including PCI-adw, PCI-adr, and PCI-ayw were injected into mice via tail vein. HBsAg and HBsAb in mice sera were tested at the first and 7th day respectively after antigen plasmids injection. Both in vitro simulation and in vivo animal models demonstrated that HBsAg antigen and HBsAb of the same serotypes Could not coexist, but HBsAg antigen and HBsAb of different serotype could coexist. HBsAg/HBsAb double positive hepatitis B virus infection could be due to infection of viruses of different serotypes.     

血清学标志阴性的慢性肝炎患者病理与临床

目的了解血清学标志阴性的慢性肝炎患者病理与临床特征。方法对62例血清学标志阴性反复肝功能异常的肝炎患者进行血清肝炎病毒学检测、肝穿刺病理和免疫组化检查、肝功能和凝血功能检查,对其中乙肝患者采用荧光定量PCR方法检测血清乙肝病毒DNA（HBVDNA）。结果62例患者临床诊断与病理诊断的符合率为53．2％,慢性肝炎轻度的符合率较高为69．1％。62例患者肝组织免疫组化检查示28例（45．2％）HBsAg和／或HBcAg阳性,可确诊为乙型肝炎。28例乙肝患者肝组织病理均有炎症病变,其中G1最高占13例（46．4％）,其次G2占10例（35．7％）,G4最少占2例（7．1％）;肝纤维化分期S0占12例（42．9％）,S1占7例（25％）,S4最少占1例（3．6％）。28例患者中10例（35．7％）检测血清HBVDNA阳性,平均（3．3±2．2）×10^3拷贝／ml,肝脏炎症分级及纤维化分期各组之间血清HBVDNA定量水平比较差异无统计学意义（P〉0．05）。HBVDNA阳性和阴性患者的各项指标比较差异无统计学意义（均P〉0．05）。乙肝患者和非乙肝患者各项指标比较差异无统计学意义（均P〉0．05）。结论血清学标志阴性HBV感染仍是我国原因不明肝病的主要病因之一,且多为慢性肝炎,HBVDNA仍低水平复制,临床表现轻,炎症分级和纤维化程度较轻,但仍可发展为肝硬化。     

慢性乙型肝炎患者HBV基因表型与血清学测定的临床意义

目的 分析慢性乙型肝炎患者HBV基因表型和血清学特征,以探讨二者的临床意义。方法 检测210例慢性乙型肝炎患者HBV DNA载量和HBV 基因亚型、HBV血清标志物HBsAg和HBeAg以及ALT水平,分析免疫耐受期、免疫清除期、低水平复制期和复发期4个时相中HBV基因亚型与血清标志物水平、HBsAg效价与HBV DNA载量、HBeAg及ALT水平的相关性。结果 慢性乙型肝炎患者HBV基因型主要为HBV DNA高载量的B2和中等载量的C2亚型,阳性率分别为59.0%和25.2%。B2亚型与HBsAg、HBeAg和ALT水平均呈显著正相关(P<0.01),C2亚型与各指标水平均无显著相关性(P<0.05)。乙型肝炎不同时相的基因亚型阳性率之间差异无统计学意义(P>0.05),但HBsAg水平与HBV DNA量、HBeAg和ALT水平分别存在不同的相关性。结论 HBV基因分型和血清学检测可早期预测慢性乙型肝炎患者长期疾病进展结果。     

Prospective evaluation of seropositive occult hepatitis B viral infection in lymphoma patients receiving chemotherapy

OBJECTIVE. To serially evaluate the viral kinetics of occult hepatitis B virus infection in lymphoma patients and perform a correlation with clinical outcomes. DESIGN. Case series with 1-year follow-up. SETTING. Regional hospital, Hong Kong. PATIENTS. Consecutive patients who were newly diagnosed to have lymphoma in the hospital between 1 April 2007 and 31 March 2008 were tested for hepatitis B (HB) surface (s) antigen (Ag), anti-HBs antibody (Ab) and anti-HB core (c) Ab. Seropositive occult hepatitis B patients as defined by being negative for HBsAg but positive anti-HBsAb and/or anti-HBcAb without a hepatitis B vaccination history were recruited. Serum HBsAg, anti-HBsAb, anti-HBcAb, hepatitis B virus deoxyribonucleic acid (DNA) level, and liver biochemistry were checked at baseline and every 4 weeks during and after chemotherapy until 12 months after the completion of chemotherapy or death. Entecavir was started if patients developed biochemical flare-up of hepatitis B associated with virological rebound. The prevalence and course of hepatitis B virus-related hepatitis, as well as any temporal relationship to viral kinetics and clinical hepatitis, were assessed. RESULTS. Of 47 patients tested, 10 (21%) with lymphoma were seropositive occult hepatitis carriers. Their median baseline hepatitis B virus DNA level was 89 IU/mL (range, <34-807 IU/mL). Virological rebound (as defined by a 10-fold increase in serum hepatitis B virus DNA level from pre-chemotherapy level persisted for 4 weeks) occurred in one of the 10 patients, followed by biochemical reactivation. Whereupon entecavir treatment was started and no liver failure ensued. Regarding the other seropositive occult patients, their serum hepatitis B virus DNA levels fluctuated, but there was no associated biochemical reactivation. CONCLUSION. Detectable baseline serum hepatitis B virus DNA is not uncommon in patients with occult hepatitis B who receive chemotherapy. Transient elevation in serum hepatitis B virus DNA levels does not predict biochemical reactivation, but antiviral treatment might be considered if virological rebound persists.     

Evidence of hepatitis virus infection among Australian prisoners of war during World War II

A sample of Australian male veterans of World War II was surveyed after 40 years. One hundred and seventy veterans had been held by the Japanese as prisoners of war and 172 veterans had served in southeast Asia but had not been taken captive (non-prisoners of war). A medical history was obtained and a physical examination undertaken. Blood was drawn and analysed for standard liver biochemistry and serological markers of hepatitis A and B virus (HAV, HBV) infections. The prevalence of immunoglobulin (Ig)G class antibodies to HAV was 95.2% in non-prisoners of war and 93.3% in prisoners of war. Only three cases of hepatitis B surface antigen (HBsAg) seropositivity were identified (two cases from the prisoner-of-war group). Thirty-six (21.8%) prisoners of war were seropositive for the presence of antibodies to HBsAg (anti-HBs) and 34 (20.0%) prisoners of war for that of antibodies to hepatitis B core antigen (anti-HBc), compared with 16 (9.8%) and eight (4.7%) of the non-prisoners of war, respectively (P = 0.002 and P = 0.0001, respectively). Those veterans who reported jaundice during World War II had a higher prevalence of antibodies to HBV. Among prisoners of war who were forced to work on the Burma-Thailand railway, 24.1% were seropositive for anti-HBc compared with 11.1% of the remaining prisoners of war (P = 0.048). It would appear that hepatitis B was common in prisoners of war but that those who survived 40 years were able to clear the virus and do not appear to have significant liver disease.     

Gianotti-Crosti syndrome associated with infections other than hepatitis B

Although the Gianotti-Crosti syndrome (GCS) is regularly associated with hepatitis B infection elsewhere, in North America that association is rarely made. Accordingly, we studied nine children with acral, symmetrical eruptions typical of GCS for evidence of other infections. All were negative for hepatitis B surface antigen. Viral cultures were done in nine patients, and viruses isolated in two. One patient with a respiratory prodrome had respiratory syncytial virus (RSV) isolated, and a second patient studied simultaneously showed serological evidence of RSV infection. A third patient with both respiratory tract and gastrointestinal tract symptoms yielded a polio-vaccine enterovirus. Two patients with fever and pharyngitis had group A beta-hemolytic streptococci isolated from the throat. Skin biopsies were done in three cases, and findings were consistent with GCS. Electron microscopy of two lesional biopsy specimens failed to demonstrate viral particles. Epstein-Barr virus serological findings were negative in six cases and showed evidence of past infection in three cases. This study strengthens the observation that hepatitis B is not the causative agent of GCS in this country and suggests that multiple infectious agents may be associated with this distinctive exanthem.     

Markers of hepatitis B virus infection in schoolchildren in the Kimberley, Western Australia

In 1986 the Aboriginal community in Western Australia was identified as a high-risk group for hepatitis B virus infection. An immunization programme was commenced in 1988 but concerns were expressed about horizontal transmission, especially in schools, to the low-risk Caucasian group and whether they should also be included in the vaccination programme. To estimate the extent of this occurrence, a survey of schoolchildren from two district high schools in Broome and Derby in the Kimberley Region of Western Australia was carried out in March 1989. A total of 607 students aged 4 to 19 years were included in the study. None of the 300 Caucasian students had any serological markers of hepatitis B virus infection (95% confidence interval (CI) upper limit, 1.3%). Eighteen children were found to be seropositive for hepatitis B surface antigen (HBsAg); 17 were Aboriginal and one Asian. In addition, 61 Aboriginal students and one Asian had hepatitis B surface antibody (antiHBs). The hepatitis B virus infection rate in these Aboriginal children is 28.2% (95% CI, 23.2%-33.7%) with a carrier rate of 6.1% (95% CI, 3.9%-9.6%). This study demonstrates that Caucasian students have a very low risk of infection with hepatitis B virus in this community, and there is therefore no need to extend the hepatitis B vaccination programme beyond the already identified high-risk groups.     

Success of a program of routine prenatal screening for hepatitis B surface antigen: the first 2 years.

Prenatal screening for hepatitis B surface antigen (HBsAg) restricted to women with defined risk factors for chronic hepatitis B virus (HBV) infection fails to identify many carriers. A centralized program of routine HBsAg screening for all pregnant women in Alberta was introduced in 1985. We collected and analysed data for the first 2 years of the program in Edmonton to determine the frequency of risk factors for HBsAg positivity, the proportion of multiparous HBsAg-positive women not identified in previous pregnancies, the efficiency and cost-effectiveness of providing immunoprophylaxis to infants at risk of HBV infection and the degree of success in inducing adequate protection. A total of 149 women (158 pregnancies) were found to be HBsAg positive. Risk factors were readily ascertainable for 85% of the women; the remaining 15% would not have been identified through risk-selective screening. The most common risk factors were Oriental ethnic origin, history of hepatitis, jaundice or multiple transfusions of blood or blood products, and occupational exposure to blood. Although 86% of the multiparous HBsAg-positive women had risk factors, only 7% had been identified in previous pregnancies. The Alberta program appears to be cost-effective. We conclude that only routine prenatal screening will identify all infants at risk of perinatal HBV infection and that a comprehensive public health program involving central laboratories, private physicians and public health staff can be highly effective and efficient in protecting infants against hepatitis B.     

乙型肝炎患者体内病毒复制水平的试验观察

目的探讨乙肝病毒感染者体内血清标志物与乙肝病毒脱氧核糖核酸（HBV—DNA）和转氨酶的相互关系及其临床意义。方法采用酶联免疫吸附试验（ELISA）检测HBV血清标志物，采用实时荧光定量PCR方法检测HBV—DNA，采用速率法测定血清内的转氨酶。结果随着病毒复制水平的增加，“大三阳”的检出率具有逐渐增加的趋势，而“小三阳”的检出率具有逐渐减少的趋势；“大三阳”与患者体内血清转氨酶异常检出率显著高于“小三阳”；在“小三阳”中，当HBV—DNA大于10^5时，转氨酶异常者的检出率显著增加，而“大三阳”中没有观察到该结果。结论“大、小三阳”可作为HBV复制和疾病进展评估的参考指标。     

Management of chemotherapy-induced hepatitis B virus reactivation

Hepatitis B virus (HBV) reactivation induced by cytotoxic chemotherapy is an important issue in cancer patients. An elevated HBV viral load usually precedes hepatitis flare, and hepatic decompensation and eventual death is not infrequent once viral reactivation is initiated. Reverse seroconversion from hepatitis B surface antigen (HBsAg)-negative to HBsAg-positive would also occur in hepatitis B core antibody (anti-HBc)-positive patients. The risk of HBV reactivation can be attributed to patient viral status and the regimen of chemotherapeutic agents. Chemotherapeutic regimens that contain steroid and rituximab can increase the risk of viral reactivation in lymphoma patients. Consequently, routine HBV marker screening, including HBsAg and anti-HBc, is mandatory prior to chemotherapy for all cancer patients, and prophylactic antiviral treatment is highly recommended for HBsAg-positive cases. However, for patients who are anti-HBc-positive and HBsAg-negative, so-called resolved hepatitis B patients, regular HBV viral load survey during the course of chemotherapy is necessary to early detect HBV reactivation. Currently, the role of antiviral prophylaxis for resolved hepatitis B patients is still unsettled.