Results of this study indicated that the extent of liver damage in CHB patients had an obvious effect on AFP serum levels. There were significant positive and moderate correlations between AFP and inflammation stages and between AFP and fibrosis stages. AFP also had a significant weak to moderate correlation with AST, ALT and GGT values (Spearman’s correlation coefficients were 0.22, 0.331, and 0.445, respectively; all p < 0.001). Overall, as pathological levels of inflammation and fibrosis increased in patients with CHB, the levels of serum AFP also increased.
Age and gender had little influence on changes in serum AFP levels in this study. Approximately 70% of CHB patients in China are infected via mother-to-child vertical transmission, making it difficult to estimate the median duration of CHB infection. Since the initial detection of CHB infection does not represent the start of infection, we used age to replace the duration of infection. Ninety percent of those infected in infancy, 50% who are infected in childhood, and even fewer over the next years of young adulthood will become chronically infected, with a high life-time risk of developing HCC . Liver pathology helps to determine prognosis, as well as to determine who should receive antiviral therapy . Patients admitted to our medical center were preparing for antiviral therapy and the aim of liver biopsy in these cases was to clarify the pathological status of the active CHB phase. Based on patient selection, inflammation and fibrosis stages increased with age, and so did AFP levels.
We showed that serum APRI values were significantly associated with inflammation stages. We excluded serum AST and ALT values from the multivariate analysis due to its co-linearity with APRI values. Importantly, we found that AFP levels increased as inflammation stages progressed. The median serum AFP values in patients at G0-G3 were within the normal range, while patients at G4 had a significant elevation of AFP median values. The correlation coefficient between AFP levels and inflammation stages (0.436) showed a moderate positive association between AFP levels and inflammation stages in CHB patients. Marked changes in serum AFP are not expected with light liver inflammation (G0 ~ 2). We observed a higher correlation between AFP and inflammation when liver inflammation was more severe.
The specific program of prevention and cure for viral hepatitis that is generally used in China  is similar to the METAVIR semiquantitative scoring system , and classifies fibrosis into 5 stages: F0 (no fibrosis), F1 (mild fibrosis without septa), F2 (moderate fibrosis with few septa), F3 (severe fibrosis with numerous septa without cirrhosis) and F4 (cirrhosis). CHB patients with significant fibrosis (METAVIR F >2) are prescribed antiviral treatment. In the present study, patients at stages S3 and S4 had a significant elevation in AFP levels, while patients at stages S0, S1 and S2 had normal AFP values. The correlation coefficient between AFP and fibrosis stages was 0.404. AFP levels also showed a moderate positive trend in relationship to fibrosis stages in CHB patients. Investigation of the relationship between AFP levels and liver stiffness using transient elastography showed similar results (correlation coefficient of 0.317 between AFP and fibrosis stages) . These data suggest that AFP plays a role in regeneration of liver tissue, and inflammation and liver fibrosis constitute an indirect index of regeneration. More inflammation is therefore linked with more regeneration, and more liver fibrosis. One critical finding of the present study was that serum AFP levels had a diagnostic value for severity of inflammation and fibrosis even in patients with “normal” levels of serum AFP. Low AFP values in some adult patients still indicated a “severe” condition, reflecting the association between AFP and liver regeneration.
We previously showed that serum ceruloplasmin (CP) levels were negatively and indirectly associated with inflammation and fibrosis, and used serum CP in combination with routinely measured clinical parameters to establish a non-invasive model to predict fibrosis . The prognostic value of a number of other biomarkers for liver fibrosis, such as FibroTest, FibroMeter, FIB-4, ELF, APRI, and FibroScan elastography, were recently investigated [25, 26], and only the FibroTest had no significant difference in prognostic value compared to liver biopsy. There has also been a recent focus on developing novel proteomic biomarkers candidates for liver fibrosis in hepatitis C . Although a number of biomarkers including albumin, platelets, hyaluronic acid and AST have been evaluated, there is currently no single marker which successfully predicts significant fibrosis in HBV-related liver disease, and multiple biomarkers are needed to complement clinical data . In the present study, we compared the prognostic value of AFP with that of liver biopsy, using a METAVIR-like scoring system . There was a direct relationship between AFP and both inflammation and fibrosis, suggesting that AFP had a prognostic value, especially given the AUROC scores in our study. The most important criteria for use of a specific non-invasive biomarker in clinical practice is the number of patients correctly classified by the method for a defined end-point based on the reference standard for the method . Based on these criteria, AFP is a promising biomarker to assess liver pathology.
To our knowledge, this is the first study to examine the relationship between serum AFP levels and the pathological status of inflammation and fibrosis in patients with CHB. Nevertheless, this study has some limitations. First, the study was done in a single medical center and the sample was relatively small. Second, we applied the accepted pathological staging system used in China but there are no known comparisons between this system and other universal systems, which may limit the value of our findings. It is important to note that the occurrence of acute flares has an important role in the progression of CHB. Differences in inflammation grade make it difficult to evaluate the performance of fibrosis biomarkers such as AFP which are strongly influenced by inflammation. Finally, serum AFP values in this study were measured at certain transverse sections of time and not dynamically. We are aware that better diagnostic values for liver pathological stages could be attained by repeated and dynamic measurement of AFP levels, and plan to address this issue in our future studies. Values for serum ALT and sonography were not included for each patient, which precludes determining the sensitivity, specificity and overall effectiveness of serum AFP in comparison to other approaches. Future studies with multiple centers and a larger sample size are needed to evaluate the prognostic value of adding AFP to the clinical scoring models currently used . Serum biomarkers have been shown to contribute only modestly to clinical predictive factors for risk assessment, indicating that potential biomarkers must be studied in cohorts with a broad distribution of fibrosis severity .