Viral level is an indicator of long-term outcome of hepatitis B virus e antigen-negative carriers with persistently normal serum alanine aminotransferase levels

Summary. The association between viral level and the long‐term outcomes of hepatitis B virus (HBV) carriers who test negative for hepatitis B virus e antigen (HBeAg) but have persistently normal serum alanine aminotransferase levels (PNALT) remains unclear. We examined hepatocarcinogenesis, hepatitis reactivation, predictive factors and the time course of HBV DNA levels during follow‐up in 104 HBeAg‐negative Japanese carriers with PNALT. During a mean follow‐up period of 6.4 ± 3.4 years, 5 patients (4.8%) had hepatocarcinogenesis and 14 (13.5%) had hepatitis reactivation. At 5 and 10 years, the cumulative rates of hepatocarcinogenesis were 2.4% and 9.9%, while those of hepatitis activation were 13.7% and 15.5%, respectively. An HBV DNA level of ≥5 log₁₀ copies/mL was the sole predictor of hepatocarcinogenesis with a univariate analysis. An HBV DNA level of ≥5 log₁₀ copies/mL and an alanine aminotransferase (ALT) level of >20 to ≤40 IU/L were independent predictors of hepatitis reactivation in a Cox model. Because there was no association between hepatocarcinogenesis and ALT activity, the HBV DNA level was considered an essential predictor. In addition, the baseline HBV DNA level was related to the future level and was not subject to wide fluctuations. Our results showed that an HBV DNA level of ≥5 log₁₀ copies/mL predicts subsequent hepatocarcinogenesis and hepatitis reactivation in HBeAg‐negative carriers with PNALT. As the baseline HBV DNA level reflects the future level, appropriate clinical management according to the viral level is expected to decrease future risk.     

Serum alanine aminotransferase level in relation to hepatitis B and C virus infections among blood donors

Abstract: To assess the serum alanine aminotransferase (ALT) activity in relation to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections among blood donors, antibodies to HCV (anti-HCV) and hepatitis B surface antigen (HBsAg) were detected in 400 blood donors with normal ALT level (≤750 μmol/s per liter), and 76 blood donors with raised ALT level. The prevalence of anti-HCV (10.5%) and HBsAg (28.9%) in the latter was higher than that (2.0% and 17.5%, respectively) in the former (p<0.001 and p<0.03, respectively). There was a trend that indicated that the risk of anti-HCV positivity increased with increasing age (p<0.001). Thirty of 76 (39.5%) donors with raised ALT level were positive for anti-HCV or HBsAg. Compared with HBsAg-positive donors, donors with anti-HCV had higher serum ALT levels (p<0.01) and greater mean age (p<0.01). Multivariate analysis indicated that both anti-HCV (odds ratio: 6.2; 95% confidence interval: 2.2–17.8) and HBsAg (odds ratio: 2.2; 95% confidence interval: 1.3–3.9) were significantly associated with raised serum ALT activity. The estimated population-attributable risk was 8.6% for anti-HCV, and 13.8% for HBsAg. In conclusion, although HBV and HCV infections are independent risk factors of raised ALT activity among blood donors, they play a minor role in the etiology of raised ALT activity.     

Molecular and serological characterization of hepatitis B virus in deferred Ghanaian blood donors with and without elevated alanine aminotransferase

Candidate blood donors in Ghana are frequent carriers of hepatitis B virus (HBV). A comparative study of 117 donor samples including 46 with alanine aminotransferase (ALT) > or = 60 IU/L and 71 with < or =40 IU/L level was undertaken. S and the basic core promoter-precore regions (BCP/PC) sequencing was used to identify genotypes and variants relevant to HBV natural history, respectively. Age, viral load, HBe status were correlated with molecular data. HBV genotype E (87%) was dominant with little genotypes A (10%) and D (3%). Comparing individuals with or without liver disease, an association between liver disease and older age (P = 0.004) and higher viral load (P = 0.002) whether as a whole population or only genotype E was found. Compared with a commercial assay, BCP/PC sequencing had lower sensitivity to detect mixtures of wild-type and variant viruses but detected BCP deletions. BCP 1762/1764 variants were positively correlated with older age (P < 0.0001) and elevated ALT levels (P = 0.01). PC 1896 stop codon was marginally correlated with viral load (P = 0.09). HBV genotype E infection natural history appears different from genotypes B and C prevalent in Asia. Donors with liver disease being older, with higher viral load and higher BCP variant proportion may be at higher risk of cirrhosis and hepatocellular carcinoma.     

Changes of serum aminotransferase activities in relation to serum hepatitis Be antigen levels in chronic type B hepatitis

The purpose of this study was to determine the level of serum hepatitis Be antigen (HBeAg) during hepatitis B virus carriage and its clinical significance. The mean level of serum HBeAg, quantitated by solid-phase enzyme immunoassay, was 5924 units in asymptomatic carriers (s.d. = 5534, n= 100), 3044 units in patients with chronic persistent hepatitis (s.d. = 4826, n= 34), 3599 units in chronic active hepatitis (s.d. = 4953, n= 45) 1348 units in liver cirrhosis (s.d. = 2379, n= 25) and 766 units in hepatocellular carcinoma (s.d. = 1257, n= 18). In the 10 HBeAg-positive patients with chronic active hepatitis, the fluctuation in HBeAg level was followed by changes in alanine aminotransferase (ALT) activity. Among the 36 peaks of HBeAg and ALT, HBeAg peaks preceded ALT peaks in 22 and simultaneous peaks were present in 14. The changes of HBeAg level were closely related to increase in disease activity as estimated by ALT activities; therefore, HBeAg quantitation can be a useful predictor of disease activity in chronic hepatitis B.     

替比夫定治疗高ALT水平HBeAg阳性慢性乙型肝炎的临床观察

目的观察替比夫定治疗高ALT水平HBeAg阳性慢性乙型肝炎（CHB）患者的疗效。方法 60例HBeAg阳性的CHB患者以ALT为依据分为低ALT组（ALT在2倍ULN与10倍之间）和高ALT组（ALT在10倍ULN与20倍之间）,给予替比夫定600 mg/d,观察治疗52周时的应答情况。结果治疗52周时,高ALT组HBV DNA降低比例明显高于低ALT组,差异有统计学意义;低ALT组HBeAg阴转率及血清学转换率、HBsAg阴转率低于高ALT组,差异有统计学意义;高ALT组中有4例出现HBsAg阴转,3例出现了HBsAb;低ALT组中没有出现HBsAg阴转及血清学转换。52周时两组患者ALT复常率、病毒学反弹、对替比夫定耐药及肌酸激酶升高水平相似。结论高水平ALT是替比夫定治疗应答较好的预测因子     

A higher alanine aminotransferase level correlates with earlier hepatitis B e antigen seroconversion in lamivudine‐treated chronic hepatitis B patients

Background/Aims: A pretherapy serum alanine aminotransferase (ALT) level above five times the upper limit of normal (ULN) is known to predict hepatitis B e antigen (HBeAg) seroconversion during lamivudine therapy for chronic hepatitis B patients. However, whether an even higher pretherapy serum ALT value or other viral factors could affect treatment responses remains unclear. Patients and methods: A total of 253 HBeAg‐positive chronic hepatitis B patients who had a pretherapy serum ALT level over five times ULN and received lamivudine for 12–18 months were retrospectively collected. Among these patients, 38% had received prior lamivudine treatment. HBeAg seroconversion was the primary endpoint of treatment. Baseline clinical and viral features were compared between responders and non‐responders at the end of treatment and 6 months post‐treatment. Results: At the end of therapy, the overall HBeAg seroconversion rate was 33.6%. For lamivudine‐naïve patients, the HBeAg seroconversion rate was 37.8%. Subgroup analysis showed that patients with pretherapy ALT levels over 10 times ULN had a significantly higher HBeAg seroconversion rate than those with a pretherapy ALT level between five and 10 times ULN at 3 months (P=0.045) and 6 months (P=0.037) of lamivudine treatment. No significant difference was found in terms of pretherapy serum ALT values, viral load and genotypes between seroconverters and non‐seroconverters. Conclusions: For lamivudine‐treated HBeAg‐positive patients with pretherapy ALT levels over five times ULN, an even higher ALT level could predict earlier HBeAg seroconversion; however, neither ALT levels nor viral factors correlate with higher response rates after 12–18 months of treatment.     

Hepatitis B surface antigen clearance in inactive hepatitis B surface antigen carriers treated with peginterferon alfa-2a

AIM: To examine the association between interferon(IFN) therapy and loss of hepatitis B surface antigen(HBs Ag) in inactive HBs Ag carriers. METHODS: This was a retrospective cohort study in inactive HBs Ag carriers, who were treatment-naive, with a serum HBs Ag level 100 IU/m L and an undetectable hepatitis B virus(HBV) DNA level( 100 IU/m L). All the 20 treated patients received subcutaneous PEG-IFN alfa-2a 180 μg/wk for 72 wk and were then followed for 24 wk. There were 40 untreated controls matched with 96 wk of observation. Serum HBs Ag, HBV DNA, and alanine aminotransferases were monitored every 3 mo in the treatment group and every 3-6 mo in the control group. RESULTS: Thirteen(65.0%) of 20 treated patients achieved HBs Ag loss, 12 of whom achieved HBs Ag seroconversion. Mean HBs Ag level in treated patients decreased to 6.69 ± 13.04 IU/m L after 24 wk of treatment from a baseline level of 26.22 ± 33.00 IU/m L. Serum HBV DNA level remained undetectable( 100 IU/m L) in all treated patients during the study. HBs Ag level of the control group decreased from 25.72 ± 25.58 IU/m L at baseline to 17.11 ± 21.62 IU/m L at week 96(P = 0.108). In the control group, no patient experienced HBs Ag loss/seroconversion, and two(5.0%) developed HBV reactivation.CONCLUSION: IFN treatment results in HBs Ag loss and seroconversion in a considerable proportion of inactive HBs Ag carriers with low HBs Ag concentrations.     

Wild-type and 'a' epitope variants in chronic hepatitis B virus carriers positive for hepatitis B surface antigen and antibody

AIMS: This study aims to examine the genomic variants of the 'a' epitope in chronic hepatitis B virus (HBV) carriers positive for both hepatitis B surface antigen (HBsAg) and antibody to HBsAg (anti-HBs). METHODS: Eighteen HBV carriers were studied. Hepatitis B virus (HBV) DNA was extracted and the 'a' epitope region was amplified and sequenced. RESULTS: Eighteen Chinese asymptomatic HBV carriers were studied. There were 13 patients who were positive for both HBsAg and anti-HBs. Of these, one patient had only wild-type HBV, three had a viral mixture, and five had only 'a' epitope variant HBV. Of the three patients with a viral mixture, all had variants in the less conserved region (123-137). Of the five patients with pure HBsAg mutants, three had variants in the less conserved region while two had variants in the highly conserved region. In this study with a limited number of patients, the serum alanine aminotransferase (ALT) levels were higher in patients with wild-type HBV, compared with those with either 'a' epitope variants or a viral mixture consisting of wild type and variants. CONCLUSION: Eight of the nine (89%) patients positive for both HBsAg and anti-HBs harbored an 'a' epitope variant. The lower ALT levels seen in patients who had either pure 'a' epitope variant or a mixture of wild type and mutants suggest that a closer monitoring of these 'a' epitope variants should be required, as patients carrying these infectious viral strains may remain asymptomatic.     

Predictors of liver histological changes and a sustained virological response to peginterferon among chronic hepatitis B e antigen‐positive patients with normal or minimally elevated alanine aminotransferase levels

A proportion of chronic hepatitis B patients with normal or only minimally elevated alanine aminotransferase (ALT) levels display significant histologic changes and would benefit from antiviral therapy. We aim to evaluate the histologic abnormalities seen in these patients and then determine which of them would most likely respond to peginterferon therapy. One hundred and thirteen hepatitis B e antigen (HBeAg)‐positive patients with a normal or minimally elevated ALT level and moderate‐to‐severe histologic changes in their liver tissue were selected to receive peginterferon monotherapy and participate in a follow‐up analysis. A multiple logistic regression analysis indicated that increasing age (P=.049) and lower hepatitis B virus (HBV) DNA levels (P=.038) were associated with significant histological abnormalities in patients with a normal or minimally elevated ALT. Our predictive model which incorporated HBeAg testing at treatment week 12 combined with hepatitis B surface antigen (HBsAg) testing at treatment week 24 was able to identify which patients with a normal ALT level would achieve a sustained virological response (SVR) (positive predictive value [PPV]: 66.7%, negative predictive value [NPV]: 90.0%). Lower HBsAg and HBeAg levels at treatment week 24 were associated with a SVR in patients with a minimally elevated ALT level (PPV: 100.0%, NPV: 100.0%). A liver biopsy and antiviral therapy should be strongly considered when treating HBeAg‐positive patients with a normal or minimally elevated ALT level, low HBV DNA level, and aged >35 years. On‐treatment quantification of combined HBsAg and HBeAg test results may be useful for predicting a SVR to peginterferon monotherapy in these patients.     

Fibrosis progression rates between chronic hepatitis B and C patients with elevated alanine aminotransferase levels

BACKGROUND: We evaluated the annual rate of fibrosis progression in chronic hepatitis B and C patients with elevated alanine aminotransferase (ALT) levels. METHODS: Forty-nine chronic hepatitis B patients and 21 chronic hepatitis C patients, each of whom had undergone two or more liver biopsies at an interval of more than 1 year, were enrolled in this retrospective clinical research protocol. The annual rate of fibrosis progression was calculated by dividing the change in fibrosis stage between the first and second liver biopsies by the interval in years between them. RESULTS: The median interval in chronic hepatitis B and C was 3.4 (first and third quartiles, 1.8-4.7) and 3.2 (2.1-6.5) years, respectively. Overall, the mean fibrosis progression rate was 0.21 +/- 0.31 (mean +/- SD) fibrosis units (FU) per year in 49 patients with chronic hepatitis B, and 0.13 +/- 0.18 FU/year in 21 patients with chronic hepatitis C. The ALT level was an independent variable correlating with fibrosis progression. In patients whose median ALT level was 70 IU/l or more, the mean fibrosis progression rate was 0.28 +/- 0.32 FU/year in 36 patients with chronic hepatitis B, and 0.22 +/- 0.23 FU/year in eight patients with chronic hepatitis C. CONCLUSION: This paired-biopsy study of untreated chronic hepatitis B or C demonstrated that fibrosis progression occurred largely in patients with continuously elevated ALT levels even over a relatively short period, and that liver fibrosis might progress by one stage within an average of 4-5 years of follow-up in patients with elevated ALT of 70 IU/l or more.     

乙型肝炎e抗原阴性慢性乙型肝炎和肝硬化患者病毒基因型及丙氨酸氨基转移酶水平分析

目的观察乙型肝炎e抗原(HBeAg)阴性慢性乙型肝炎(CHB)及肝硬化患者的乙型肝炎病毒(HBV)基因型及丙氨酸氨基转移酶(ALT)水平。方法采用酶联免疫吸附法检测62例CHB和41例肝硬化患者HBV标志物和血清ALT水平,用聚合酶链反应法检测其HBV基因型。结果CHB患者中,21 例(33.9%)为HBeAg阴性,41例(66.1%)为HBeAg阳性;肝硬化患者中,28例(68.3%)为HBeAg阴性,13例(31.7%)为HBeAg阳性。CHB患者中,53例(85.5%)为C基因型,9例(14.5%)为B基因型; 肝硬化患者中39例(95.1%)为C基因型,2例(4.9%)为B基因型。HBeAg阴性CHB患者ALT>40 U/L 者的比例低于HBeAg阳性组(分别为47.6%和85.4%),差异有统计学意义(P<0.01)。HBeAg阴性肝硬化患者ALT>40 U/L者的比例低于HBeAg阳性组(分别为64.3%和92.3%)但差异无统计学意义。结论CHB 和肝硬化患者中,HBeAg阴性者的比例较高,此类患者的ALT水平较低,以C基因型占优势。     

Are alanine aminotransferase,hepatitis B virus DNA or IgM antibody to hepatitis B core antigen serum levels predictors of histological grading in chronic hepatitis B?

Abstract: Paired sera and liver biopsies from 105 patients with chronic hepatitis B virus infection (34 HBeAg positive and 71 anti-HBe positive) were studied to investigate the relation between the degree of histological activity and alanine aminotransferase (ALT), hepatitis B virus DNA (HBV-DNA) or IgM antibody to hepatitis B core antigen (IgM anti-HBc) levels. ALT levels were significantly higher in patients with piecemeal necrosis (155±124 vs 75±42, p=0.0017), but there were no differences in the ALT values of patients with or without intralobular necrosis. ALT values were within normal range in 29% of 31 patients without versus 15% of 65 with piecemeal necrosis (p=0.19). Serum HBV-DNA levels were not related to the grade of lobular or portal/periportal activity in HBeAg-positive patients. Anti-HBe-positive subjects with piecemeal necrosis had higher HBV-DNA levels (34±93 vs 4±6, p=0.01). IgM anti-HBc indexes were significantly higher in patients with intralobular necrosis (0.635±0.600 vs 0.356±0.367, p=0.0005) or piecemeal necrosis (0.671 ±0.633 vs 0.321 ±0.219, p=0.0002). In summary, since serum IgM anti-HBc-IMx indexes can reflect the grade of histological activity, the quantitative assessement of this antibody could be useful for non-invasive monitoring of hepatocellular damage in chronic hepatitis B.     

The effects of antiviral agents on serum hepatitis B e antigen levels in chronic type B hepatitis

In the present study, aiming at the evaluation of the effects of antiviral therapy on hepatitis B e antigen (HBeAg) levels, serum HBeAg concentration was determined serially by a quantitative assay in 44 patients with chronic hepatitis B who received a total of 73 courses of antiviral treatment. The posttreatment HBeAg levels were significantly lower than pretreatment baseline in all treated groups, not only at the end of treatment but also 6 months after the completion of therapy. The proportional decrease in treated patients was significantly greater than in 15 untreated controls. Six months after the completion of treatment, serum HBeAg became negative in seven out of 25 treatments with interferon, seven out of 28 with adenine arabinoside, and five out of 20 with adenine arabinoside 5'-monophosphate. All patients who became negative for HBeAg had normalization of alanine aminotransferase as well. A progressive decrease in HBeAg in patients treated with multiple courses of drug was observed, and the frequency of negative tests increased, paralleling the number of courses of treatment. These results suggest that antiviral therapy may alleviate inflammatory changes in the liver by promoting clearance of HBeAg from the serum, and may eventually shorten the natural course of hepatitis associated with chronic hepatitis B virus infection.     

补肾健脾方对HBeAg阳性乙肝病毒携带者的抗病毒疗效

目的:评价补肾健脾方对HBeAg阳性HBV携带者的抗病毒疗效及安全性。方法:采用多中心、随机、双盲、安慰剂对照的临床研究方法。300例e-抗原阳性乙肝病毒携带者随机双盲分入两个试验组,其中治疗组200例,对照100例。52周的双盲治疗期间,治疗组患者给予补肾健脾方治疗,对照组患者给予安慰剂治疗,以上药物均为颗粒冲剂,用法均为1剂/d,分两次开水冲服。治疗过程中检测患者血清HBV DNA定量及乙肝两对半定量并观察不良反应的发生。结果:治疗52周时治疗组患者血清HBV DNA水平明显下降,与0周及安慰剂对照组比较,差异有显著性意义;其中治疗组下降>1 lg及>2 lg的比例为45.98%、21.84%,明显多于对照组的11.83%、5.38%。治疗过程中,治疗组患者HBeAg均值、HBsAg均值均呈持续下降趋势。52周时,治疗组患者HBeAg均值、HBsAg均值下降均显著优于安慰剂对照组,差异有显著性意义;而HBsAg下降>0.5 lg的百分率治疗组、对照组分别为22.99%、7.53%,差异有显著性意义。52周时,两组患者血清HBV DNA水平下降>3 lg及阴转比例,HBeAg阴转率以及HBeAg血清转换比例,HBsAg下降>1 lg、>2 lg及阴转比例相似,差异均无显著性意义。研究过程中,各组均未发生任何严重不良事件。结论:补肾健脾方有一定的抑制HBV的作用,作用呈时间依赖趋势。     

Efficacy of telbivudine in HBeAg-positive chronic hepatitis B patients with high baseline ALT levels

AIM:To evaluate the efficacy and safety of telbivudine(LDT) in hepatitis B e antigen(HBeAg)-positive chronic hepatitis B(CHB) patients who have high baseline alanine aminotransferase(ALT) levels between 10 and 20 times the upper limit of normal.METHODS:Forty HBeAg-positive CHB patients with high baseline ALT levels between 10 and 20 times the upper limit of normal were enrolled and received LDT monotherapy for 52 wk.Another forty patients with baseline ALT levels between 2 and 10 times the upper limit of no...     

Clinical importance of serum hepatitis B surface antigen levels in chronic hepatitis B

Quantitative serology for hepatitis B surface antigen (HBsAg) is a new candidate marker for prediction of clinical outcome. The aim of this study was to investigate the clinical significance of quantifying HBsAg in patients with hepatitis B virus (HBV) infection. A total of 424 patients who tested positive for HBsAg and were referred to Chiba University Hospital between January 1985 and April 2008 were included in the study, and the following characteristics were analyzed: age, gender, status of hepatitis B e antigen (HBeAg), alanine aminotransferase level (ALT), HBV DNA level, number of platelets and development of hepatocellular carcinoma. Measurement of HBsAg was performed using the chemiluminescent enzyme immunoassay method. The study group consisted of 239 men and 185 women, and their average age was 40.6 ± 14.0 years. HBsAg showed a positive correlation with HBV DNA level (Pearson's product moment correlation, r = 0.586, P < 0.001) and a weak inverse correlation with age (r = 0.3325, P < 0.001). A control study, matched with age and sex, was performed between two groups with and without HBeAg seroconversion during follow-up period. Compared with the age and sex-matched controls, the change in HBsAg levels per year showed a significant decrease 2 years before seroconversion (paired t-test, P < 0.05). The serial measurement of quantitative HBsAg level has the possibility of predicting the occurrence of HBeAg seroconversion.     

血清低水平丙氨酸氨基转移酶的HBV感染者临床特征分析*

目的 分析总结低水平血清丙氨酸氨基转移酶(ALT)的HBV感染者临床特征,以利于寻找肝功能可能已经异常的线索。方法 2017年1月～2021年3月我院诊治的HBV感染者226例,均接受肝活检,采用Scheuer评分系统和组织学活动指数评价肝组织纤维化分期和炎症活动度分级。将肝组织炎症活动度分级和肝纤维化分期≥G2S2定义为显著肝组织学病变。结果 在本组226例HBV感染者中,临床诊断HBV携带者125例,慢性乙型肝炎(CHB)患者101例;CHB患者男性占比、显著肝组织病变、血清AST水平>40 U/L、肝纤维化分期≥F2和肝组织炎症活动度≥G2分别为77.2%、61.4%、49.5%、36.7%和52.5%,显著高于HBV携带者的54.4%、33.6%、5.6%、18.4%和25.6%(P<0.05);在226例HBV感染者中,经肝组织学检查,发现显著肝组织病变104例,非显著肝组织病变122例;显著肝组织病变患者血清HBV DNA水平为(4.6±1.2)lg copies/ml,显著低于非显著组【(5.2±1.4)lg copies/ml,P<0.05】,外周血血小板计数为(163.6±49.2)×10⁹/L,显著低于非显著组【(192.2±54.5)×10⁹/L,P<0.05】,血清ALT水平>40 U/L、AST水平>40 U/L、肝纤维化分期≥F2和肝组织炎症活动度分级≥G2占比分别为60.6%、39.4%、57.7%和81.7%,显著高于非显著组(分别为31.1%、13.1%、0.0%和0.0%,P<0.05)。结论 对于血清ALT低水平的HBV感染者应进行临床资料的筛查和甄别,其中一些已经存在肝组织学病变,适时进行肝活检可以帮助早期发现CHB患者而给予必要的处理,以改善预后。