The diagnostic value of transient elastography combined with serum SAA and IL-6 in the degree of hepatitis B liver fibrosis

XU Bin, SUN Long

1.Department of Infectious Disease, the First Affiliated Hospital of Hainan Medical College, Haikou 570102,China

Keywords:

ABSTRACT Objective:To investigat the diagnostic value of transient elastography combined with serum amyloid A and interleukin-6 in the degree of hepatitis B liver fibrosis.Methods:A total of 334 patients with chronic HBV infection that were admitted to the Department of Infectious Diseases of the First Affiliated Hospital of Hainan Medical College from January 2020 to May 2022 with informed consent and underwent liver biopsy puncture were selected.According to the pathological results, they were divided into no obvious fibrosis group, obvious fibrosis group and liver cirrhosis group.Comparison of liver stiffness measurement (LSM), serum amyloid A(SAA0, IL-6 levels between different groups.This study drawed was conducted draw the receiver operating characteristic (ROC) curve of each index to diagnose significant liver fibrosis and liver cirrhosis, and compared the area under the ROC curve (AUC) and diagnostic efficacy of each non-invasive fibrosis diagnostic model.The diagnostic performance of the combined assay was superior to that of APRI and FIB-4 In different degrees of liver fibrosis.Results:According to the degree of liver fibrosis, the levels of SAA, IL-6, and LSM in the no significant fibrosis group (n=140), the significant fibrosis group (n=134), and the cirrhosis group (n=60) were statistically significant difference(All P＜0.001).SAA, IL-6 and LSM were significantly correlated with the degree of liver fibrosis(rs=0.456, rs=0.482, rs=0.602,All P＜0.001).The AUC of SAA and IL-6 for the diagnosis of significant fibrosis in hepatitis B were 0.738 and 0.809, respectively.And the AUC for the diagnosis of liver cirrhosis were 0.813 and 0.823, respectively.The AUC for the combined diagnosis of significant fibrosis and cirrhosis were 0.930 and 0.964, respectively.The diagnostic performance of the combined assay was superior to that of APRI and FIB-4 in different degrees of liver fibrosis(All P＜0.001).Conclusion:LSM combined with serum SAA and IL-6 has great diagnostic value for different degrees of hepatitis B liver fibrosis.

1.Introduction

Liver fibrosis is the excessive deposition of liver fibrous connective tissue caused by various chronic liver damage, and is also an important link in the process of liver disease [1, 2].Significant liver fibrosis is an important condition for antiviral treatment of chronic hepatitis B (CHB) [3-5].The gold standard for the diagnosis of liver fibrosis is liver biopsy [2], but its invasiveness leads to difficulties in clinical development.Non-invasive liver fibrosis detection technology has always been a hot spot in clinical research.transient elastography (TE) to detect liver stiffness measurement (LSM) has a good diagnostic efficiency in the diagnosis of liver fibrosis in CHB patients.However, the actual application is affected by liver inflammation, liver steatosis, alanine aminotransferase and bilirubin levels, ascites, intercostal space size and other factors, resulting in certain differences in the results.The combination of serological indicators can further improve the diagnostic efficiency of TE [6-9].serum amyloid A (SAA), which is mainly synthesized in white fat and hepatocytes, is one of the main acute phase proteins of human beings [10-13].Some studies have reported that the expression level of SAA is significantly increased in chronic viral hepatitis, but there is no relevant report on liver fibrosis [12, 14, 15].interleukin-6 (IL-6)is a proinflammatory cytokine.Some studies have shown that the expression of serum IL-6 is up-regulated in patients with hepatitis B virus (HBV) infection.In addition, serum IL-6 in CHB patients is closely related to the degree of liver function damage and disease progression [16-21].This study explored the correlation between LSM, serum SAA and IL-6 of TE technology and different degrees of liver fibrosis in hepatitis B, so as to provide a certain clinical basis for the diagnosis of non-invasive liver fibrosis.

2.Objects and Methods

2.1 Object

Patients with newly diagnosed chronic hepatitis B who were admitted to the Department of Infectious Diseases, the First Affiliated Hospital of Hainan Medical College from January 2020 to May 2022, signed informed consent and underwent liver biopsy were selected.According to the Metavir scoring system, F0-1 was divided into the non-significant fibrosis group, F2-3 was the significant fibrosis group, and F4 was the cirrhosis group [2, 5].All patients were excluded from autoimmune hepatitis, alcoholic liver disease, fatty liver disease, drug-induced liver damage, other hepatotropic viruses and other extrahepatic diseases, such as other bacterial or viral infections, diabetes, extrahepatic tumors, cardiovascular diseases.ALT＞5ULN.This study was approved by the Ethics Committee of the First Affiliated Hospital of Hainan Medical College (Approval No.2020 (Research) No.(18)).

2.2 Methods

Hematological tests were performed within 48 hours before liver biopsy in all patients, all of which were morning fasting venous blood.Alanine aminotransferase (ALT), aspartate aminotransferase(AST), interleukin-6 (IL-6) and serum amyloid A (SAA) were detected.The four items of liver fibrosis included hyaluronic acid(HA), procollagen type 3 N-terminal peptide (P Ⅲ P), collagen type IV (CIV) and laminin (L.N).The LSM of all patients was measured by ultrasonographer using transient elastic scanner (FS), and liver biopsy was performed, and the degree of liver fibrosis was scored by pathologist.

2.3 Method of statistics

MedCalc 20.0 software was used for statistical analysis.Measurement data that did not conform to normal distribution were represented by M(P25,P75), and comparison between groups was performed by Kruskal-Wallis H rank sum test.Enumeration data were expressed as the rate or constituent ratio, and comparison between groups was performed by chi-square test.Spearman correlation analysis was used to analyze the correlation between each diagnostic index and the degree of liver fibrosis.The diagnostic value was evaluated by ROC curve, and the AUROC was calculated.The AUROC and performance of the noninvasive diagnostic model were compared by Delong test.In order to P＜0.05 was considered statistically significant.

3.Result

3.1 The general information

A total of 334 patients were enrolled.There were 204 males (61.1%)and 130 females (38.9%).According to the degree of liver fibrosis,the patients were divided into no significant fibrosis group (n=140),significant fibrosis group (n=134) and cirrhosis group (n=60).There were significant differences in age, SAA, IL-6, LSM and HA levels among the three groups (P＜0.05).Table 1.

3.2 Correlation of serological indexes and LSM with the degree of liver fibrosis

SAA, IL-6 and LSM were positively correlated with the degree of liver fibrosis, and the correlation coefficients were 0.453, 0.482 and 0.602(P＜0.001).Table 2.

Tab 1 Comparison of general information in patients

Tab 2 Correlation analysis of serological indexes and LSM with the degree of liver fibrosis

3.3 SAA, IL-6 and LSM have significant diagnostic efficacy in liver fibrosis

The AUC of SAA, IL-6 and LSM in the diagnosis of significant liver fibrosis were 0.738, 0.809 and 0.817, respectively, and the cutoff values were 12.89 mg/L, 5.29 pg/ml and 8.0 kpa, respectively.LSM had the highest sensitivity (89.6%) and IL-6 the highest specificity (87.8%).The AUC of SAA, IL-6 and LSM in pairwise combined detection of significant liver fibrosis was higher than that of single index.The AUC of combined detection was 0.930, the sensitivity and specificity were 88.8% and 81.4%, respectively.Table 3, Figure 1, Figure 2.

3.4 Efficacy of SAA, IL-6 and LSM in diagnosis of liver cirrhosis

The AUC of SAA, IL-6 and LSM were 0.813, 0.823 and 0.901,respectively, and the cut-off values were 14.13 mg/L, 5.44 pg/mL and 9.4 kpa, respectively.LSM had the highest sensitivity(91.7%) and IL-6 had the highest specificity (88.6%).The AUC of SAA+LSM was 0.945, and the sensitivity and specificity were 86.7% and 87.9%, respectively.The AUC was 0.964, the sensitivity and specificity were 83.3% and 95.0%, respectively.Table 4, Figure 3, Figure 4.

Fig 3 ROC curve of single index in the diagnosis of liver cirrhosis

Fig 4 Combined detection of ROC curve in the diagnosis of liver cirrhosis

Table 4 The efficacy of SAA, IL-6 and LSM in the diagnosis of liver cirrhosis

Table 5 The comparison of AUROC between combined detection and LSM,APRI and FIB-4

Fig 1 ROC curve of single index in the diagnosis of significant liver fibrosis

Fig 2 Combined detection of ROC curve in the diagnosis of significant liver fibrosis

Tab 3 The efficacy of SAA, IL-6 and LSM in the diagnosis of significant liver fibrosis

3.5 The AUROC of combined detection was compared with LSM, APRI and FIB-4

The efficacy of combined detection in the diagnosis of significant fibrosis and cirrhosis was significantly higher than that of LSM,APRI and FIB-4(P＜0.001).

4.Discussion

It is particularly important to correctly evaluate the degree of liver fibrosis in CHB patients and to grasp the timing of anti-hepatitis B virus therapy.Due to the limitations of liver biopsy, the diagnosis of non-invasive fibrosis in CHB patients is currently a hotspot.In this study, the AUROC of TE alone in the diagnosis of significant liver fibrosis and cirrhosis were 0.817 and 0.901, which were similar to the 0.863 and 0.918 reported by Huang[22], indicating that TE has a good diagnostic efficacy for liver fibrosis in CHB patients, and its diagnostic accuracy increases with the degree of liver fibrosis.In this study, the cut-off value for the diagnosis of significant liver fibrosis was 8.0 kpa, and the cut-off value for the diagnosis of liver cirrhosis was 9.4 kpa, which had a certain gap with the reference range proposed in the guidelines, which may be influenced by the age,body size, intercostal space width and other factors of the enrolled patients [1, 2].

LSM combined with single or multiple serological indicators can improve the diagnostic efficiency of liver fibrosis and cirrhosis to a certain extent [23, 24].SAA and IL-6, as common clinical indicators,are involved in the formation of liver fibrosis and the occurrence and development of HBV-related diseases [14, 21, 25, 26].This study also verified the diagnostic value of SAA and IL-6 in liver fibrosis and cirrhosis in CHB patients, which provides a new reference index for evaluating the degree of liver fibrosis in CHB patients.After analyzing the correlation between SAA, IL-6 and the degree of liver fibrosis in CHB patients, the results showed that SAA, IL-6 were positively correlated with the degree of liver fibrosis (rs= 0.456,0.482,P＜0.001), suggesting that SAA and IL-6 were moderately correlated with the degree of liver fibrosis.

In addition, this study showed that the AUROC of LSM, SAA and IL-6 combined in the diagnosis of significant fibrosis and cirrhosis in CHB patients was higher than that of single index, and its diagnostic efficacy was significantly higher than that of LSM and traditional serological models APRI and FIB-4 (P＜0.001).The diagnostic efficacy of TE and serological indicators alone is limited, and the combination of SAA and IL-6 on the basis of TE can be used as a model for the non-invasive diagnosis of hepatitis B liver fibrosis.The in vivo serological and in vitro liver hardness value detection can make up for the lack of mutual diagnostic performance, and reduce the instability of a single detection method.

This study also has some limitations.Firstly, this study is based on the evaluation of newly treated CHB patients, and its applicability to the treated population needs to be further verified.Secondly,the sample of this study was from a single center, and there was selection bias, so the multi-center study was not conducted.

In conclusion, this study shows that transient elastography combined with SAA and IL-6 has certain application value in evaluating the degree of liver fibrosis in patients with CHB initially treated, and has a guiding role in the timing of anti-hepatitis B virus therapy in such patients.

Author contribution

Xu Bin conceived and designed the paper, collected and collated data, and wrote the paper.Sun Long is responsible for the quality control and proofreading of the article, and is overall responsible for the article.

There are no conflicts of interest in this article.