Prediction models of hepatocellular carcinoma development in chronic hepatitis B patients

Chronic hepatitis B virus(HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma(HCC). Applying the same strategies for antiviral therapy and HCC surveillance to all chronic hepatitis B(CHB) patients would be a burden worldwide. To properly manage CHB patients, it is necessary to identify and classify the risk for HCC development in such patients. Several HCC risk scores based on risk factors such as cirrhosis, age, male gender, and high viral load have been used, and have negative predictive values of ≥ 95%. Most of these have been derived from, and internally validated in, treatment-na?ve Asian CHB patients. Herein, we summarized various HCC prediction models, including IPM(Individual Prediction Model), CU-HCC(Chinese University-HCC), GAG-HCC(Guide with Age, Gender, HBV DNA, Core Promoter Mutations and Cirrhosis-HCC), NGM-HCC(NomogramHCC), REACH-B(Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B), and Page-B score. To develop a noninvasive test of liver fibrosis, we also introduced a new scoring system that uses liver stiffness values from transient elastography, including an LSM(Liver Stiffness Measurement)-based model, LSM-HCC, and mR EACH-B(modified REACH-B).     

Natural history of chronic hepatitis B REVEALed

Chronic hepatitis B is a worldwide public health challenge. Knowledge of natural history of chronic hepatitis B is important for the management of the disease. A community-based prospective cohort study was carried out to evaluate the risk predictors of progression of chronic hepatitis B in Taiwan. A total of 23,820 participants were enrolled in 1991-1992 from seven townships in Taiwan. Their serum samples were collected at study entry and tested for hepatitis B surface antigen (HBsAg) and e antigen (HBeAg), antibodies against hepatitis C virus (anti-HCV), alanine aminotransferase (ALT), and α-fetoprotein (AFP). A subcohort of 3653 male and female participants who were seropositive for HBsAg and seronegative for anti-HCV was included in the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study. Newly developed cases of cirrhosis and hepatocellular carcinoma (HCC) were ascertained through follow-up examination and data linkage with profiles of the National Cancer Registry, National Health Insurance Database and Death Certification System. The incidence of both HCC and cirrhosis were significantly associated with serum HBV DNA levels in a dose-response relationship from <300 (undetectable) to ≥1,000,000 copies/mL. The biological gradients remained significant (P<0.001) after adjustment for age, sex, habits of cigarette smoking and alcohol drinking, HBeAg serostatus, and serum ALT level at cohort entry. A significant association with risk of cirrhosis and HCC was also observed for HBV genotype, precore G1896A mutant and basal core promoter A1762T/G1764A double mutant. Nomograms have been developed for the long-term risk prediction of cirrhosis and HCC for patients with chronic hepatitis B. Inactive carriers of HBV have an increased HCC incidence and liver-related mortality than HBsAg-seronegative controls. Serum HBV DNA level at study entry is a major predictor of spontaneous seroclearance of HBeAg, HBV DNA and HBsAg. These findings may inform the effective and efficient management of chronic hepatitis B.     

Evaluation of serum clusterin as a surveillance tool for human hepatocellular carcinoma with hepatitis B virus related cirrhosis

Background and Aim: Hepatocellular carcinoma (HCC) is a common human cancer worldwide. The levels of serum clusterin in HCC patients and its potential diagnostic significance is not clear. We aimed to evaluate the clinical use of serum clusterin levels as a surveillance tool for HCC with hepatitis B virus (HBV) related cirrhosis. Methods: Twenty‐two cases of healthy subjects, 31 cases of HBV carriers, 26 patients with chronic hepatitis B, 29 patients with cirrhosis, and 76 patients with HCC were enrolled in this study. Serum levels of clusterin were measured by a sandwich enzyme‐linked immunosorbent assay. Results: The serum clusterin levels in HCC patients were significantly lower than that in healthy, HBV carriers and chronic hepatitis B, but statistically higher than in cirrhosis patients. Receiver operator characteristic (ROC) curve indicated that a serum clusterin value of 50 µg/mL yielded the best sensitivity (91%) and specificity (83%) for differentiating HCC patients with HBV‐related cirrhosis from those with HBV‐related cirrhosis. The optimal alpha fetoprotein (AFP) cutoff value was 15 ng/mL and was inferior to the clusterin value of 50 µg/mL, the area under the ROC curves being 0.937 versus 0.781, respectively (P < 0.05). Conclusions: Serum clusterin was more sensitive and specific than serum AFP for differentiating HCC patients with HBV‐related cirrhosis from those with HBV‐related liver cirrhosis, and may be a useful surveillance tool of HCC based on HBV‐related cirrhosis.     

Risk for hepatocellular carcinoma in the course of chronic hepatitis B virus infection and the protective effect of therapy with nucleos(t)ide analogues

Hepatocellular carcinoma(HCC) is a major health problem worldwide, representing one of the leading causes of death. Chronic hepatitis B virus(HBV) infection(CHB) is the most important etiologic factor of this tumor, accounting for the development of more than50% of the cases in the world. Primary prevention ofHCC is possible by hepatitis B vaccination conferring protection from HBV infection. However, according to the World Health Organization Hepatitis B Fact sheet N° 204(update of July 2014) globally there exists a large pool of 240 million people chronically infected with HBV who are at risk for development of HCC. These individuals represent a target population for secondary prevention both of cirrhosis and of HCC. Since ongoing HBV replication in CHB is linked with the progression of the underlying liver disease to cirrhosis as well as with the development of HCC, effective antiviral treatment in CHB has also been evaluated in terms of secondary prevention of HCC. Currently, most patients with active CHB are subjected to long term treatment with the first line nucleos(t)ide analogues entecavir and tenofovir. These compounds are of high antiviral potency and have a high barrier to HBV resistance compared to lamivudine, adefovir dipivoxil and even telbivudine. Many studies have shown that patients under antiviral treatment, especially those in virological remission, develop less frequently HCC compared to the untreated ones. However, the risk for development of HCC cannot be eliminated. Therefore, surveillance for the development of HCC of patients with chronic hepatitis B must be lifelong or until a time in the future when new treatments will be able to completely eradicate HBV from the liver particularly in the early stages of CHB infection. In this context, the aim of this review is to outline the magnitude of the risk for development of HCC among patients with CHB, in the various phases of the infection and in relation to virus, host and environmental factors as evaluated in the world literature. Moreover, the benefits of antiviral treatment of CHB with nucleos/tide analogs, which have changed the natural history of the disease and have reduced but not eliminated the risk of HCC are also reviewed.     

AFP、AFP-L3％、GP73在肝硬化、肝癌患者血清中的表达及鉴别诊断价值

目的：探讨不同血清肿瘤标志物在肝硬化和肝癌的鉴别诊断中的临床价值。方法回顾性分析146例肝硬化患者、50例原发性肝癌患者的临床资料,并选取50例健康体检者作为对照,分别检测血清AFP、甲胎蛋白异质体（AFP-L3）和高尔基体糖蛋白73（GP73）含量,并计算 AFP-L3％。结果146例肝硬化患者的 AFP 阳性率为平均25．3％,低于肝癌组的72％（χ2＝34．69,P＜0．01）;AFP-L3％在不同病因肝硬化组中阳性率均较低,平均8．9％,低于肝癌组的58％（χ2＝53．32,P＜0．01）,也低于肝硬化组中AFP 的阳性率（χ2＝13．90,P＝0．0002）;GP73在不同病因肝硬化组、肝癌组阳性率均较高,在肝硬化组中平均阳性率为74．7％,高于AFP 及AFP-L3％在肝硬化组中的阳性率（χ2＝71．01,P＜0．01）,与GP73在肝癌组中的阳性率比较差异无统计学意义（χ2＝0．84,P＝0．36）。AFP、AFP-L3％的敏感性、特异性均较GP73好,联合诊断不能提高鉴别准确性。结论血清肿瘤标志物AFP 在乙型肝炎肝硬化及隐源性肝硬化患者中阳性率较高,AFP-L3％在各种病因肝硬化患者中均较低,AFP、AFP-L3％可有效区分肝癌和肝硬化;GP73在不同病因肝硬化组中均高,不能用于区分肝硬化和肝癌。     

Hepatitis B-related hepatocellular carcinoma: epidemiological characteristics and disease burden

Summary. Worldwide, 350 million people are chronically infected with hepatitis B virus (HBV) who are at greater risk of hepatocellular carcinoma (HCC) compared with uninfected people. The relative risks of HCC among people infected with HBV ranges from 5 to 49 in case–control studies and from 7 to 98 in cohort studies. More than 50% of HCC cases worldwide and 70–80% of HCC cases in highly HBV endemic regions are attributable to HBV. Incidence of HCC (per 100 000 person/year) among people with chronic HBV infection ranges from 400 to 800 in male and from 120 to 180 in female. Factors associated with increased risk of HCC include demographic characteristics (male sex and older age), lifestyles (heavy alcohol consumption and smoking), viral factors (genotype C, D F, high level of HBV DNA, core/precore mutation) and clinical factors (cirrhosis, elevated alpha‐fetoprotein (AFP) and alanine aminotransferase (ALT)). HBV‐related HCC has extremely poor prognosis with median survival less than 16 months. Survival rates of HBV‐related HCC ranged from 36% to 67% after 1 year and from 15% to 26% after 5 year of diagnosis. Older age, liver function impairment, vascular invasion, tumour aggressiveness and elevated AFP are associated with HCC survival. Global burden of HBV‐related liver disease is still a major challenge for public health in the 21st century. While decreases in incidence of HBV infection have been observed in birth cohorts following the introduction of universal infant HBV vaccination programme, HBV‐related HCC incidence in is projected to increase for at least two decades because of the high prevalence of chronic HBV infection and prolonged latency to HCC development. To reduce HBV‐related HCC continued expansion of universal infant HBV vaccination is required along with antiviral therapy targeted to those individuals at highest risk of HCC. Broad public health strategies should include routine testing to identify chronic HBV infection, improved health infrastructures including human resource to provide diagnosis and treatment assessment.     

Correlation of liver biochemistry with liver stiffness in chronic hepatitis B and development of a predictive model for liver fibrosis

Aim: To correlate liver stiffness with demographical factors and routine liver biochemistry and to assess the predictive value of these as potential markers of fibrosis. Methods: Transient elastography was performed in 1268 chronic hepatitis B (CHB) patients. According to a previous validated study for CHB, liver stiffness of >8.1 and >10.3 kPa were used as cut‐off values for defining severe fibrosis and cirrhosis respectively. Results: Liver stiffness correlated positively with bilirubin, alkaline phosphatase (ALP), γ‐glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), globulin, α‐fetoprotein (AFP) and HBV DNA levels and negatively with albumin and platelet levels (P<0.05 for all correlations). From 13 parameters (age, sex, platelet, AST, ALT, GGT, AFP, albumin, globulin, bilirubin, ALP, HBV DNA and hepatitis B e‐antigen), four best parameters (AST, platelet, GGT and AFP) were used to derive a liver stiffness model. Using log (index)=1.44+0.1490(GGT)+0.3308 log (AST)−0.5846 log (platelets)+0.1148 log (AFP+1) to predict both severe fibrosis and cirrhosis had area under the receiver operating characteristics curve of 0.85. Conclusion: Routine liver biochemistry correlated well with liver stiffness in Asian CHB patients. A model using simple serum markers can predict liver stiffness, and further studies are required to validate the usefulness of these simple tests as non‐invasive markers of fibrosis in CHB.     

Cumulative incidence and risk factors for the development of hepatocellular carcinoma in patients with chronic hepatitis B who achieved sustained disappearance of viremia by nucleos(t)ide analog treatment

Aim

Nucleos(t)ide analog (NA) therapy has been reported to reduce the risk of hepatocellular carcinoma (HCC). However, some patients who achieve hepatitis B virus (HBV)‐DNA disappearance from serum by NA develop HCC. In this study, we investigated the cumulative incidence and risk factors for HCC in patients with chronic hepatitis B (CHB) who achieved sustained disappearance of viremia by NA treatment.

Methods

A total of 133 CHB patients (median age, 51 years; 79 men [59%]; 28 with cirrhosis [21%]) who received NA therapy and achieved HBV‐DNA disappearance from serum were analyzed retrospectively. We evaluated the cumulative incidence of HCC and risk factors associated with HCC based on data collected at the time of HBV‐DNA disappearance.

Results

Thirteen patients developed HCC during the follow‐up period. The 1‐, 3‐, and 5‐year cumulative incidence of HCC was 0.0%, 7.8%, and 11.1%, respectively. In multivariate analysis, advanced age (hazard ratio [HR], 4.601; 95% confidence interval [CI], 1.220–17.351; P = 0.024), liver cirrhosis (HR, 5.563; 95% CI, 1.438–21.519; P = 0.013), and higher HBV core‐related antigen (HBcrAg) levels (HR, 13.532; 95% CI, 1.683–108.815; P = 0.014) at the time of HBV‐DNA disappearance were significantly associated with the development of HCC.

Conclusion

Our findings indicate the importance of continuous HCC surveillance especially in patients with advanced age, cirrhosis, and/or higher serum levels of HBcrAg, even if they achieve HBV‐DNA disappearance.     

中国北方地区321例乙型肝炎病毒相关肝细胞癌患者的流行病学和临床特征分析

背景:我国是肝细胞癌(HCC)高发区,其中大部分HCC与乙型肝炎病毒(HBV)感染相关,有必要对其自然史和临床进程作大样本调查研究。目的:了解中国北方地区HBV相关HCC患者的流行病学和临床特征。方法:对中国北方地区321例HBV相关HCC患者作流行病学问卷调查,行肝功能、甲胎蛋白(AFP)、HBV血清标志物和HBV DNA水平检测,并进行统计分析。结果:321例HBV相关HCC患者中,仅7.2%接受过抗病毒治疗;46.4%和25.5%分别有肝硬化和肝癌家族史;38.3%有饮酒史。21.0%的患者乙型肝炎e抗原(HBeAg)阳性,62.3%乙型肝炎e抗体(HBeAb)阳性,HBeAg阳性者合并肝硬化的比例和HBV DNA水平较高。84.5%的患者HBV DNA阳性,但其中仅42.6%HBV DNA≥5.0log10,HBV DNA高水平者合并肝硬化的比例显著高于HBV DNA低水平者。无症状HBV感染、慢性乙型肝炎、代偿性和失代偿性肝硬化患者分别占4.1%、24.1%、39.0%和32.9%。71.0%的患者AFP升高,但其中仅33.8?P≥400ng/ml。结论:本组HBV相关HCC患者中,HBeAg阳性和高HBV DNA水平者不多,但病情常较重。肝硬化是HCC的重要危险因素,饮酒和肝癌家族史对HCC的发生有一定影响。血清AFP筛查有助于HCC的诊断。     

Long‐term outcome and hepatocellular carcinoma development in chronic hepatitis B or cirrhosis patients after nucleoside analog treatment with entecavir or lamivudine

Aim: We conducted this prospective study to elucidate the long‐term outcome and incidence of hepatocellular carcinoma (HCC) development after nucleos(t)ide analog (NA) treatment in patients with chronic hepatitis B (CHB) or cirrhosis. Methods: CHB or cirrhosis patients without past NA treatment or HCC were started on entecavir (ETV) or lamivudine (LVD), and prospectively followed up with monthly blood tests, and with abdominal imaging every 6 months in CHB and every 3 months in cirrhosis patients. Results: A total of 256 subjects with CHB (n = 194) or cirrhosis (n = 62) received ETV (n = 129) or LVD (n = 127) for 4.25 years (range: 0.41–10.0). After NA treatment, serum HBV DNA, alanine aminotransferase and α‐fetoprotein (AFP) dropped significantly, along with significant increases in serum albumin and prothrombin time. Drug‐resistance developed in 60 cases in the LVD group and in only one case in the ETV group. HCC developed in 35 patients, and the incidence at years 1, 3, 5, 7 and 10 was significantly higher in patients with cirrhosis (8.1%, 17.5%, 43.2%, 46.7% and 53.4%, respectively) than chronic hepatitis (1.6%, 3.5%, 3.5%, 7.1% and 29.6%, respectively), with no difference between ETV and LVD. After NA treatment, the sensitivity/specificity for HCC of AFP and des‐γ‐carboxy prothrombin (DCP) was 45.7%/97.3% and 33.3%/96.2%, respectively, with the specificity of AFP being higher than at baseline (64.4%), at the cut‐off of 10 ng/mL. Conclusion: NA exerted a long‐term efficacy and improved hepatic reservation in CHB and cirrhosis. After NA treatment, AFP dropped to lower than 10 ng/mL with marked elevation of specificity, leading to an earlier detection of HCC.     

Natural history of chronic hepatitis B: what exactly has REVEAL Revealed?

Chronic hepatitis B virus (HBV) infection is a serious public health problem because of its worldwide prevalence and potential to cause adverse consequences. The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer‐Hepatitis B Virus (REVEAL‐HBV) study carried out in Taiwan was used to investigate the natural history of chronic hepatitis B. The REVEAL‐HBV study has established an HBV viral load paradigm in the natural history of chronic hepatitis B (CHB). Serum HBV DNA level has been shown to be significantly and independently associated with incidence of hepatocellular carcinoma (HCC) and cirrhosis and liver‐related mortality across a biological gradient. It is also a major predictor of HBsAg seroclearance. Genetic features including HBV genotype and basal core promoter A1762T/G1764A mutant, and precore G1896A mutant were documented as predictors of HCC risk. Inactive HBV carriers still had an increased risk on HCC development and liver‐related mortality compared with HBsAg ‐seronegatives. Nomograms focusing on facilitating risk communication between patients and clinicians were developed incorporating non‐invasive clinical parameters to predict long‐term HCC risk. These will hopefully contribute to evidence‐based decisions in the clinical management of CHB patients. A somewhat provocative and novel finding from the REVEAL‐HBV study is the association of chronic HBV infection in active replication with an increased pancreatic cancer risk especially in women less than 50 years old. This finding will hopefully spur further research in this area seeking confirmatory evidence. Finally, we hope that the REVEAL‐HBV study will continue to be a source of data to answer other important questions in chronic hepatitis B research going forward.     

Does antiviral therapy for hepatitis B and C prevent hepatocellular carcinoma?

Approximately 75% to 80% of hepatocellular carcinomas (HCC) worldwide are attributed to chronic hepatitis B virus (HBV) and chronic hepatitis C virus (HCV) infection. Thus, effective prevention of HBV and HCV infection and progression from acute HBV and HCV infection to chronic hepatitis, cirrhosis and HCC might prevent as many as 450,000 deaths from HCC each year. The most effective approach to preventing HCC is to prevent HBV and HCV infection through vaccination. Indeed HBV vaccine is the first vaccine demonstrated to prevent cancers. However, a vaccine for HCV is not available and for persons who are chronically infected with HBV or HCV, antiviral therapy is the only option for preventing HCC. Direct evidence supporting a benefit of antiviral therapy on the prevention of HCC has been shown in a few randomized controlled trials. There is abundant evidence that antiviral therapy, in patients with long-term virological response, can improve liver histology, providing indirect support that antiviral therapy may prevent HCC by slowing progression of liver disease and possibly even reversing liver damage. Nevertheless, the risk of HCC remains in patients with chronic HBV or chronic HCV infection if treatment is initiated after cirrhosis is established. These data indicate that treatment might be of greater benefit if instituted earlier in the course of chronic hepatitis B or C. Safer, more effective, and more affordable antiviral therapies are needed for both hepatitis B and hepatitis C so more patients can benefit from treatment and more HCCs can be prevented.     

慢性HBV感染及其相关肝病患者外周血T细胞亚群的变化

目的观察不同临床类型HBV感染者外周血T淋巴细胞亚群的差异,探讨HBV对人体T细胞免疫的影响及其可能机制,不同类型慢性HBV感染者免疫失衡的规律。方法用流式细胞仪技术检测患者外周血T细胞亚群。慢性HBV感染者318例,其中HBV携带者8例,慢性乙型肝炎231例,肝炎后肝硬化61例,原发性肝癌18例,观察患者的T淋巴细胞亚群、HBV DNA等。同时收集22名健康志愿者的新鲜血检测T淋巴细胞亚群。结果不同临床类型HBV感染者外周血CD3＋T、CD4＋T、CD8＋T细胞百分数低于正常对照组,差别均有统计学意义（P〈0.05或P〈0.01）,CD4＋/CD8＋比正常对照组低,但差异均无统计学意义（P〉0.05）。结论慢性HBV感染随着病情进展,由慢性肝炎→肝硬化→肝癌,直至细胞免疫功能逐渐衰退。慢性HBV感染的不同阶段的细胞免疫紊乱各具特点,就不同类型患者应采用不同的免疫调节治疗手段。     

Pathogenesis of hepatitis B and C-induced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is estimated to have an annual worldwide incidence of 0.25 to 1.2 million new cases per year. Both the prevalence and incidence of HCC vary markedly as a function of geography and the local prevalence of chronic viral hepatitis. Both chronic hepatitis B and chronic hepatitis C are recognized as risk factors for HCC. The prevalence of cirrhosis in individuals with HCC and chronic hepatitis B or C is reported to be 80.9% and 75.8%, respectively. HCC occurs at a lower rate in chronic viral hepatitis in the absence of cirrhosis. Moreover, hepatitis C virus (HCV) rather than hepatitis B virus (HBV) is associated with the majority of non-cirrhotic cases of HCC. It is probable that the ongoing process of hepatocyte necrosis and liver cell renewal coupled with inflammation, which is characteristic of chronic viral hepatitis, causes not only nodular regeneration and cirrhosis but also progressive genomic errors in hepatocytes as well as unregulated growth and repair mechanisms leading to hepatocyte dysplasia and, in some cases, hepatic carcinoma. Current concepts concerning virus-induced HCC are reported and discussed in the following review.     

血清ALT与慢性乙型肝炎、肝硬化FibroScan 弹性值动态检测结果的相关性

目的探讨肝脏弹性值（LSM）在慢性乙型肝炎发作过程中的变化及ALT对LSM影响。方法 43名慢性乙型肝炎感染者,包括慢性乙型肝炎（CHB）23人、肝炎肝硬化（LC）20人;入院时行腹部B超检查,住院期间每7～10天、出院后每1～3月行Fibroscan（FS）检测,同时行常规血液指标化验。结果 CHB组中LSM与ALT有显著相关性（r=0.324,P=0.004）,偏相关分析提示LSM与ALT无统计学相关性（r=0.190,P=0.098）;随ALT下降,LSM逐渐降至诊断肝硬化界值14.6 kPa以下,呈现持续下降、先升后降或下降后波动等三种模式。LC组中,LSM与ALT无统计学相关性;在ALT好转的11例中,LSM较入院当天下降（P=0.003）,但仍高于肝硬化临界值。结论在非肝硬化CHB患者中,LSM受ALT水平影响较大。动态观察单一患者ALT与LSM变化,可能提高LSM预测肝纤维化准确性。     

Long-term follow-up of cumulative incidence of hepatocellular carcinoma in hepatitis B virus patients without antiviral therapy

BACKGROUNDChina has a high prevalence of hepatitis B virus (HBV), but most chronic hepatitis B (CHB) patients do not receive standardized antiviral therapy. There are few relevant reports addressing the outcomes of the large number of CHB patients who do not receive antiviral therapy.AIMTo observe the outcomes of long-term follow-up of patients with CHB without antiviral treatment.METHODSThis study included 362 patients with CHB and 96 with hepatitis B cirrhosis without antiviral treatment and with only liver protection and anti-inflammatory treatment from 1993 to 1998. The median follow-up times were 10 and 7 years, respectively. A total of 203 CHB and 129 hepatitis B cirrhosis patients receiving antiviral therapy were selected as the control groups. The median follow-up times were 8 and 7 years, respectively. Kaplan-Meier curves were used to analyze the cumulative incidence of hepatocellular carcinoma (HCC), and the Cox regression model was used to analyze the risk factors for HCC.RESULTSAmong the patients in the non-antiviral group, 16.9% had spontaneous decreases in HBV DNA to undetectable levels, and 32.8% showed hepatitis B e antigen (HBeAg) seroconversion. In the antiviral group, 87.2% of patients had undetectable HBV DNA, and 52% showed HBeAg seroconversion. Among CHB and hepatitis B cirrhosis patients, the cumulative incidence rates of HCC were 14.9% and 53.1%, respectively, in the non-antiviral group and were 10.7% and 31.9%, respectively, in the antiviral group. There was no difference between the two groups regarding the CHB patients (P = 0.842), but there was a difference between the groups regarding the hepatitis B cirrhosis patients (P = 0.026). The cumulative incidence rates of HCC were 1.6% and 22.3% (P = 0.022) in the groups with and without spontaneous HBeAg seroconversion, respectively. The incidence rates of HCC among patients with and without spontaneous declines in HBV DNA to undetectable levels were 1.6% and 19.1%, respectively (P = 0.051). There was no difference in the cumulative incidence of HCC between the two groups regarding the patients with drug-resistant CHB (P = 0.119), but there was a significant difference between the two groups regarding the patients with cirrhosis (P = 0.004). The Cox regression model was used for regression of the corrected REACH-B score, which showed that alanine aminotransferase > 400 U/L, history of diabetes, and family history of liver cancer were risk factors for HCC among men aged > 40 years (P < 0.05). Multifactorial analysis showed that a family history of HCC among men was a risk factor for HCC.CONCLUSIONAntiviral therapy and non-antiviral therapy with liver protection and anti-inflammatory therapy can reduce the risk of HCC. Antiviral therapy may mask the spontaneous serological response of some patients during CHB. Therefore, the effect of early antiviral therapy on reducing the incidence of HCC cannot be overestimated.     

慢性乙型肝炎和肝硬化患者血清HBV基因型分析

目的 分析慢性乙型肝炎和肝硬化患者血清乙型肝炎病毒(HBV)分型分布情况。方法 2015年6月～2018年5月南京中医药大学附属南京市第二医院就诊的慢性乙型肝炎患者261例,乙型肝炎肝硬化患者30例,肝细胞癌4例,采用测序法检测血清HBV基因型。结果 在295例HBV感染者中,有132例(44.7%)为B型感染,161例(54.6%)为C型感染,2例(0.7%)为D型感染;慢性乙型肝炎患者与肝硬化患者血清TBIL、ALT和AST水平比较差异均无统计学意义(P>0.05);肝硬化患者血清肝纤维化指标(P<0.05)、血清HBV DNA载量(P<0.05)和血清HBeAg阳性率(x²=5.798,P<0.05)均显著高于慢性乙型肝炎患者;乙型肝炎肝硬化患者和肝细胞癌患者C型感染比例均显著高于慢性乙型肝炎患者,差异具有统计学意义(P<0.05)结论 慢性乙型肝炎和肝硬化患者HBV感染以B基因型和C基因型为主,而肝硬化患者以C型感染居多,提示C型感染患者可能比B型患者更容易出现严重的肝损伤,并产生严重的临床结局。     

Basal core-promoter mutant of hepatitis B virus and progression of liver disease in hepatitis B e antigen-negative chronic hepatitis B.

BACKGROUND/AIMS: The long-term outcomes in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B are distinct from those in HBeAg-positive chronic hepatitis. However, the molecular virological factors that contribute to the progression of liver disease in this special clinical setting remain largely unknown. We thus investigated the association of hepatitis B virus (HBV) genotypes as well as precore/basal core-promoter mutations with the clinical and virological characteristics of patients with HBeAg-negative chronic hepatitis B in Taiwan. METHODS: HBV genotypes and sequences of precore and basal core-promoter regions of the HBV genome were determined in 174 HBeAg-negative chronic HBV infection patients including 62 inactive carriers and 112 with different stages of liver disease. RESULTS: HBV carriers with older age (> 50 years) (odds ratio, 9.09; 95% confidence interval (CI), 3.22-25, P < 0.001) and basal core-promoter mutant of HBV (odds ratio, 4.12; 95% CI, 1.41-12.03, P = 0.01) were associated with the development of liver cirrhosis and hepatocellular carcinoma (HCC). The gender-related risk factors associated with the development of liver cirrhosis and HCC were further analyzed, and basal core-promoter mutant was only associated with the development of liver cirrhosis and HCC in male carriers (odds ratio, 4.35; 95% CI, 1.30-14.52, P = 0.02). CONCLUSIONS: The risk of development of liver cirrhosis and HCC is significantly increased in patients with advanced age as well as with basal core-promoter mutant of HBV. In addition, basal core-promoter mutant might contribute to the gender difference of the progression of liver disease in HBeAg-negative chronic hepatitis B in Taiwan.     

Sarcopenia in chronic viral hepatitis: From concept to clinical relevance

Although the frequency of metabolic risk factors for cirrhosis and hepatocellular carcinoma (HCC) is increasing, chronic hepatitis B (CHB) and chronic hepatitis C (CHC) remain the most relevant risk factors for advanced liver disease worldwide. In addition to liver damage, hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are associated with a myriad of extrahepatic manifestations including mixed cryoglobulinaemia, lymphoproliferative disorders, renal disease, insulin resistance, type 2 diabetes, sicca syndrome, rheumatoid arthritis-like polyarthritis, and autoantibody production. Recently, the list has grown to include sarcopenia. Loss of muscle mass or muscle function is a critical feature of malnutrition in cirrhotic patients and has been found in approximately 23.0%-60.0% of patients with advanced liver disease. Nonetheless, among published studies, there is significant heterogeneity in the aetiologies of hepatic diseases and measurement methods used to determine sarcopenia. In particular, the interaction between sarcopenia, CHB and CHC has not been completely clarified in a real-world setting. Sarcopenia can result from a complex and multifaceted virus-host-environment interplay in individuals chronically infected with HBV or HCV. Thus, in the present review, we provide an overview of the concept, prevalence, clinical relevance, and potential mechanisms of sarcopenia in patients with chronic viral hepatitis, with an emphasis on clinical outcomes, which have been associated with skeletal muscle loss in these patients. A comprehensive overview of sarcopenia in individuals chronically infected with HBV or HCV, independent of the stage of the liver disease, will reinforce the necessity of an integrated medical/nutritional/physical education approach in the daily clinical care of patients with CHB and CHC.     

Molecular characteristics and stages of chronic hepatitis B virus infection

Hepatitis B virus （HBV） is a common viral pathogen that causes a substantial health burden worldwide. Remarkable progress has been made in our under- standing of the natural stages of chronic HBV infection. A dynamic balance between viral replication and host immune response is pivotal to the pathogenesis of liver disease. Knowledge of the HBV genome organization and replication cycle can unravel HBV genotypes and molecular variants, which contribute to the heterogeneity in outcome of chronic HBV infection. Most HBV infections are spontaneously resolved in immunocompetent adults, whereas they become chronic in most neonates and infants at a great risk of developing complications such as cirrhosis and hepatocellular carcinoma （HCC）. Those with chronic HBV infection may present in one of the four phases of infection： immune tolerance, immune clearance [hepatitis B e antigen （HBeAg）-positive chronic hepatitis B （CHB）], inactive carrier state, and reactivation （HBeAg-negative CHB）. Understanding the dynamic nature of chronic HBV infection is crucial in the management of HBV carriers. Long-term monitoring and optimal timing of antiviral therapy for chronic HBV infection help to prevent progression of HBV-related liver disease to its later stage, particularly in patients with higher risk markers of HCC, such as serum DNA concentration, HBeAg status, serum aminotransferase, HBV genotypes, and pre-core or core mutants.