Diagnostic potential of serum direct markers and non‐invasive fibrosis models in patients with chronic hepatitis B

Aim: Liver biopsy is recommended in the majority of patients with chronic viral hepatitis for fibrosis evaluation. Because of the disadvantages of liver biopsy, many studies related to non‐invasive biomarkers and scores have been performed. In this study, we aimed to assess the diagnostic value of serum direct markers and non‐invasive fibrosis models to predict liver fibrosis in the treatment‐naive chronic hepatitis B (CHB) patients and to compare their diagnostic performance. Methods: This study included 58 patients with a diagnosis of CHB virus infection and 30 healthy controls. Hyaluronic acid, tissue inhibitor of matrix metalloproteinase 1 and amino‐terminal propeptide of type III procollagen were measured by enzyme‐linked immunosorbent assay; and the Original European Liver Fibrosis panel, the Enhanced Liver Fibrosis (ELF) panel, PP score, aspartate aminotransferase to platelet ratio index (APRI) and FIB‐4 indexes were calculated using the formulas taken from previous publications. Fibrosis stage was determined using Ishak's scoring system. Results: The fibrosis stages identified upon liver biopsy was F0 in 12 patients (20.7%), F1–2 in 36 (62.1%) and F3–5 in 10 (17.2%). The diagnostic value of all the non‐invasive indices was low to detect mild fibrosis. We demonstrated that the diagnostic accuracy of HA is the best for predicting fibrosis of F3 or more (area under the receiver–operator curve, 0.902). In our study, the results from a combination of tests showed that ELF and APRI had the highest diagnostic value sensitivity of 90%, specificity of 100%, positive predictive value of 100% and negative predictive value of 96.4% for detection of fibrosis of F3 or more. Conclusion: In CHB patients, combination of ELF and APRI has a better diagnostic value in predicting fibrosis of F3 or more.     

Role of quantitative hepatitis B core antibody levels in predicting significant liver inflammation in chronic hepatitis B patients with normal or near‐normal alanine aminotransferase levels

Aim

Chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) levels are not free from significant hepatic lesions. Recently, there has been an improved understanding of the clinical significance of quantitative hepatitis B core antibody levels (qAnti‐HBc) during CHB management. In this cross‐sectional study, we evaluated the utility of qAnti‐HBc in identifying significant liver inflammation in CHB patients.

Methods

A total of 469 patients (training set, n = 363; validation set, n = 106) who underwent liver biopsy (LB) were included. The qAnti‐HBc levels were quantified and the relationship between histology and serum markers was systematically analyzed.

Results

In the training set, qAnti‐HBc levels were found to have significant diagnostic value for moderate to severe liver inflammation (≥G2) in all patients (area under the receiver operating characteristic curve [AUROC] = 0.768; 95% confidence interval [CI], 0.721–0.810; P < 0.001) and in patients with normal or near‐normal ALT levels (AUROC = 0.767; 95% CI, 0.697–0.828; P < 0.001). Our novel index (AC index) for the identification of ≥G2 inflammation, which combined the qAnti‐HBc and ALT levels, significantly improved diagnostic performance (AUROC = 0.813; 95% CI, 0.768–0.852) compared to the use of ALT alone (AUROC = 0.779; 95% CI, 0.732–0.821) in all patients. In the validation set, the AC index showed an improved AUROC of 0.890 (95% CI, 0.814–0.942) and 0.867 (95% CI, 0.749–0.943) in all patients and patients with normal ALT levels, respectively.

Conclusions

The qAnti‐HBc level predicts significant liver inflammation well, even in patients with normal or near‐normal ALT levels. Compared with the conventional ALT level, the AC index is a more reliable non‐invasive biomarker for significant liver inflammation in CHB patients.     

Approach to the patient with chronic hepatitis B and decompensated cirrhosis

Patients with chronic hepatitis B virus (HBV) can develop progressive fibrosis, cirrhosis and hepatocellular carcinoma. Patients with chronic HBV and cirrhosis are at risk of developing hepatic decompensation and have high mortality without antiviral therapy and/or liver transplantation. Treatment of chronic HBV with antiviral therapy is indicated in all patients with cirrhosis whatever the HBe‐antigen status and serum alanine aminotransferase (ALT), so that hepatic decompensation can be prevented. Initiating antiviral therapy in patients with decompensated cirrhosis can improve liver function, Child‐Turcotte‐Pugh (CTP) and model for end‐stage liver disease (MELD) scores, as well as the need for liver transplantation and mortality. Patients with chronic HBV and cirrhosis who do not respond to antiviral therapy with normalization of ALT may have a co‐existent liver disorder. One of the most common co‐existent liver disorders present in patients with chronic HBV is non‐alcoholic fatty liver disease (NAFLD). Patients with chronic HBV, NAFLD and cirrhosis may be at risk of developing decompensated cirrhosis and require a liver transplant. If patients with chronic HBV require liver transplantation, infection of the liver graft with HBV can be prevented with antiviral therapy.     

Previously unrecognized advanced liver disease unveiled by transient elastography in patients with Haemophilia and chronic hepatitis C

Summary. Before the introduction of viral inactivation procedures and viral screening of plasma‐products, haemophiliacs were at high risk of infection with HCV. Those who acquired HCV infection in the 1980s, and are still alive today, may have developed significant liver fibrosis or cirrhosis. However, liver biopsy has not routinely been utilized in the evaluation of haemophiliacs with HCV in Denmark. The aim of this study was to investigate the prevalence of significant fibrosis/cirrhosis among haemophiliacs as evaluated by transient elastography (TE). Cross‐sectional investigation of adult patients with haemophilia A or B. TE with liver stiffness measurements (LSM) ≥8 kPa were repeated after 4–6 weeks. Significant fibrosis and cirrhosis was defined as measurements ≥8 kPa or ≥12 kPa respectively. Among 307 patients with haemophilia A or B registered at the two Haemophilia centres, 141(46%) participate in this study. Forty (28.4%) had chronic hepatitis C, 33 (23.4%) past hepatitis C and 68 (48.2%) had never been infected, at screening LSM ≥8 kPa were found in 45.7%, 24.7% and 4.6% respectively. Among patients with chronic hepatitis C significant fibrosis was confirmed in 17.1% and cirrhosis in 2.9% by repeated LSM ≥8 and ≥12 kPa respectively. The median TE‐value in never HCV‐infected haemophiliacs was comparable with what has been found in healthy non‐haemophiliacs. In Danish haemophiliacs where liver biopsy has not routinely been used for assessing severity of liver fibrosis, LSM identified advanced liver disease in one‐fifth of cases that had not been recognized during clinical follow‐up.     

Changes in serum chitinase 3‐like 1 levels correlate with changes in liver fibrosis measured by two established quantitative methods in chronic hepatitis B patients following antiviral therapy

Aim

Non‐invasive assessment of changes in liver fibrosis is still an unmet medical need in the era of antiviral therapy. Therefore, we explore whether chitinase 3‐like 1 (CHI3L1), a serum marker of liver fibrosis, can be used as a non‐invasive surrogate marker of fibrosis change during treatment.

Methods

We correlated serum CHI3L1 levels with liver tissue collagen proportionate area (CPA) in a cohort of 131 patients with chronic hepatitis B (CHB) receiving entecavir‐based antiviral therapy for 78 weeks. In addition, we compared this marker with the liver stiffness measurement (LSM). Multivariate regression analyses were undertaken to determine the clinical factors associated with the CHI3L1 levels.

Results

Before treatment, correlation analysis showed that there were positive correlations between CHI3L1 levels and the CPA (r = 0.351, P < 0.001), and between CHI3L1 and LSM (r = 0.412, P < 0.001). After 78 weeks treatment, serum CHI3L1 levels decreased compared with that at baseline (87.8 vs. 69.6 ng/mL, P < 0.001), and CHI3L1 levels were also correlated with CPA (r = 0.293, P = 0.001) and LSM (r = 0.443, P < 0.001). Furthermore, there were positive correlations between the changes in CHI3L1 and CPA (r = 0.366, P<0.001), and changes in CHI3L1 and LSM (r = 0.438, P<0.001). Multivariate regression analyses indicated that CPA values were related with pre‐ (β = 5.450, P = 0.019) and post‐treatment CHI3L1 levels (β = 7.460, P = 0.023).

Conclusions

Chitinase 3‐like 1 is not only a useful non­invasive marker for the assessment of liver fibrosis in CHB patients before treatment, but also a potential useful marker for monitoring the change in liver fibrosis during therapy.     

慢性乙肝病毒感染者血清血管内皮生长因子的研究

目的:检测慢性乙型肝炎病毒感染患者血清中血管内皮生长因子(VEGF)的水平,探讨其临床意义.方法:采用双抗体夹心ELISA法对50例肝细胞癌、40例乙型肝炎肝硬化、36例乙型肝炎肝纤维化、40例慢性乙型肝炎患者血清中VEGF进行检测,并以43例健康者作为对照.同时采用全自动生化分析仪检测所有人员的肝功能常规指标.结果:慢性乙型肝炎、肝纤维化、肝硬化、肝细胞癌组患者血清VEGF浓度明显高于正常对照组(P＜0.01,P＜0.05,P＜0.05,P＜0.05),同时四组患者之间比较,差异均有统计学意义(P＜0.05).四组患者血清VEGF水平与肝功能指标AST、ALT无相关性,与GGT成正相关(r=0.337,P＜0.05).结论:VEGF与慢性乙型肝炎病毒感染者病情密切相关,可作为病情发展动态监测的指标.VEGF与GGT联合检测,可显著提高肝细胞癌的检出率.     

Characteristics of chronic hepatitis B patients who underwent liver biopsies

Summary. Significant liver disease has been reported in chronic hepatitis B patients with normal alanine aminotransferase (ALT) but most studies performed biopsies on selected patients only. The aims of this study were to determine the rate of liver biopsy, characteristics of patients who underwent a biopsy and factors associated with significant liver disease in a cohort of such patients. Records of patients with chronic hepatitis B during a 10‐year period were reviewed. Significant liver disease was defined as Knodell HAI ≥ 7 and/or Ishak fibrosis ≥ 3. Of 743 patients, 55.7% were Asian, 56.4% were men, and the mean age was 43.1 years. One hundred and ninety‐three (26%) had undergone a biopsy. Biopsied patients were more likely to be men, HBeAg positive, and had lower platelet and higher alkaline phosphatase, bilirubin, ALT and hepatitis B virus (HBV) DNA. Significant liver disease was observed in 20% of patients who had normal ALT at presentation, 14% of those with normal ALT at the time of biopsy and in none of the patients with persistently normal ALT. Patients with normal ALT who were biopsied had higher HBV DNA and higher ALT than those not biopsied. Multivariate analysis showed that low albumin at the time of biopsy and HBV DNA >5 log₁₀ copies/mL were predictors of significant liver disease. Significant liver disease is rare in patients with chronic HBV and persistently normal ALT and liver histology of chronic HBV infected patients with normal ALT cannot be generalized to other patients with normal ALT that were not biopsied.