In this study, we established a noninvasive model to predict liver histology to determine moderate or severe inflammation or significant fibrosis, and to guide the decision-making of antiviral treatment in patients with chronic hepatitis B with ALT < 2 ULN. The results showed that AST, anti-HBC and GGT were independent risk factors for antiviral therapy. The combination of AST, anti- HBC and GGT has better diagnostic performance than single variable.
In patients with chronic hepatitis B, persistent liver inflammation is a major risk factor for the development of cirrhosis, HCC and end-stage liver disease [1, 12]. The latest guidelines suggest that early and timely control of liver inflammation to prevent disease progression to end-stage liver disease is the primary task of liver fibrosis detection. The latest EASL guidelines point out that antiviral therapy should be performed when ALT > ULN. The AASLD guidelines indicate that patients with ALT > ULN but < 2 ULN need to consider the severity of liver histological changes. Therefore, it is very important to evaluate the progress of liver inflammation and fibrosis in the early stage for the treatment and prognosis in the later stage. At present, ultrasound-guided percutaneous liver biopsy still remains the gold standard to evaluate the severity of liver injury . However, this is an invasive operation with related complications, and its clinical application is limited .Therefore, our research is to avoid the clinical need of liver biopsy by establishing noninvasive, repeatable and rapid indicators of antiviral treatment decision-making.
Serum ALT level is one of the main biochemical markers to evaluate liver inflammation. A study in a Korean population showed that some people with high viral load and ALT < 2 ULN had significant liver necrosis inflammation and fibrosis . About 37% of CHB patients with normal or near normal ALT level, but had significant liver histologic changes[18, 19] . The results showed that ALT level was not enough to assess the severity of liver injury . Some studies have shown that AST has better diagnostic performance than ALT in predicting hepatic necrotizing inflammation . As an independent factor to predict significant fibrosis, AST level increased with the aggravation of liver fibrosis . Some of the delay clearance in AST was related to ALT level , and some of the advanced liver fibrosis was related to mitochondrial damage . Another study suggested that the increase of AST level was related to the advanced fibrosis . Our study shows that AST level can better predict moderate and severe inflammation and significant fibrosis. Therefore, we should be closely monitored and evaluated AST level regularly.
Some studies have suggested that anti-HBC in serum biomarkers is a sensitive marker in the history of chronic HBV infection. After the appearance of HBsAg in the early stage of HBV infection, anti-HBC antibodies will be detected in serum soon [25, 26]. Serum anti-HBC level is closely related to the state of HBsAg and the activity of liver inflammation . In patients with chronic hepatitis B whose ALT level is less than 2 ULN, the serum anti-HBC level has a better diagnostic performance in predicting moderate and severe liver inflammation, even in patients with normal or slightly elevated ALT level [20, 21]. Li et al founded that the anti-HBC level increased with gradually severity of hepatic inflammation and fibrosis stage. Anti-HBC showed a high diagnostic accuracy for identifying moderate or severe inflammation in all patients and patients with ALT lower than 64 IU/L (AUROC = 0.768 and 0.767, respectively) in a study of 469 treatment-naïve CHB patients. In our study, Anti-HBC is a major predictor of liver fibrosis, which has good diagnostic performance in predicting liver inflammation and necrosis.
In patients with chronic hepatitis B, GGT as an independent variable has a higher diagnostic performance for significant fibrosis . GGT is more stable in predicting liver inflammation than ALT and AST. GGT is an important predictor of noninvasive fibrosis in patients with HBV infection [28–30]. Therefore, GGT is a reliable predictor of liver histological changes in routine laboratory indexes. We should regularly monitor the dynamic changes of this index and give drug treatment when necessary.
The nomogram not only reflects the predicted value of each variable, but also reflects the complex interaction with other variables . Through constructing the model, clinicians can more accurately assess the incidence of liver fibrosis, so as to provide guidance for better monitoring and treatment of patients with chronic hepatitis B.
According to logistic analysis, we set up a new combined model, which combines AST, anti-HBC and GGT. This combined model is simple and easy to use, and has a good effect on the decision-making of antiviral therapy. Through ROC curve analysis, the combined index is 0.700 and 0.742 in training set and verification set respectively, which is higher than AST, anti-HBC and GGT. If AGH index is higher than the high critical value, antiviral therapy is recommended; if AGH index is lower than the low critical value, regular follow-up is recommended; if AGH index is between the low and high critical value, liver biopsy is recommended.
Our research has its own advantages. AGH model is a new index, which is composed of clinical routine laboratory tests and easy to obtain. It is suitable for most patients with chronic hepatitis B virus infection as well as be used to predict liver histology to avoid the need of liver biopsy. There have some defects in this model. Firstly, the number of patients included is small, the clinical application should be included in a large number of patients for multicenter cohort study. Secondly, we constructed the model in the training set and randomly select another group in the same center to verify, but we insist that the credibility of the model can be enhanced by the validation in the multicenter study. In addition, our results are not compared with other methods, and the value of compared with other methods need further study.
In conclusion, our study shows that AST, Anti-HBC and GGT are independent variables in the decision-making of antiviral therapy for chronic hepatitis B. AGH model which is a new combined index, has a good diagnosis performance. It can provide a noninvasive prediction model for CHB patients to choose antiviral therapy, liver biopsy or regular follow-up, and help to reduce the clinical needs of liver biopsy.