Caspase-cleaved fragments of cytokeratin-18 as a marker of inflammatory activity in chronic hepatitis B virus infection

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Abstract

Background

The differential diagnosis between inactive carrier and active hepatitis is important in patients with chronic hepatitis B (CHB) virus infection. Serum cytokeratin (CK)-18 fragments (M30-antigen) are proposed as biomarkers of apoptosis.

Objectives

We investigated whether serum M30-antigen levels might help to characterize the various phases of CHB and predict the state of significant inflammation in patients with CHB.

Study design

A total of 339 CHB patients who underwent liver biopsy, were included. Serum M30-antigen levels were compared between inactive carriers (n = 21), patients with HBeAg-negative hepatitis (n = 95), HBeAg-positive hepatitis (n = 141) and liver cirrhosis (n = 82).

Results

Serum M30-antigen levels were correlated significantly not only with AST (r = 0.544, p < 0.001) and ALT (r = 0.315, p < 0.001) and but also inflammatory grading score on liver biopsy (r = 0.240, p < 0.001). Serum M30-antigen level in HBeAg-negative CHB was significantly higher than that of inactive HBV carrier (399.78 U/L vs 148.90 U/L, p < 0.001). Multivariate analysis showed that AST (p < 0.001), albumin (p = 0.009) and M30-antigen (p = 0.020) were the independent predictors of significant inflammation. Combined serum M30-antigen level (>344 U/L) and AST (>78 IU/L) measurement provided the most accurate identification of significant inflammation, showing 38.2% sensitivity, 96.1% specificity, 91.0% positive predictive value and 56.1% negative predictive value.

Conclusions

Serum M30-antigen can be a predictive marker for distinguishing between inactive carrier and HBeAg-negative CHB. Serum M30 levels are associated with the presence of significant inflammation, especially in patients with normal or minimally elevated ALT in CHB patients.

Section snippets

Background

Chronic hepatitis B virus (HBV) infection remains a serious public health problem affecting more than 400 million people worldwide [1]. According to the natural history, chronic HBV carriers can be presented with various clinical states as inactive HBV carriers, individuals with hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis B (CHB), or with liver cirrhosis [2]. Inactive HBV carriers have low levels of HBV-DNA and normal serum aminotransferase and are at low risk to

Objectives

The aim of this study was to investigate whether serum levels of caspase-generated fragments of CK-18 may provide useful information on the extent of liver injury in various clinical conditions of HBV infection. Furthermore, we explored whether serum M30-antigen level can be used to predict significant necroinflammation in patients with CHB.

Patients

A total of 339 patients with chronic HBV infection were prospectively recruited from 6 medical centers (Ajou University Hospital, Hallym University Chuncheon, CHA University Hospital, Inje University Busan Paik Hospital, Pusan National University Hospital and Catholic University St. Vincent's Hospital) in South Korea from October 2005 to June 2009. All patients underwent liver biopsy and had not received antiviral treatment within 6 months prior to this study's enrollment. Patients were not

Patient characteristics

The baseline characteristics of the enrolled patients are outlined in Table 1. Three hundred and thirty-nine patients (234 men and 105 women) between 18 and 70 years of age (mean, 42.98 ± 18.10 years) were included. The distribution of inflammatory activity grades and fibrosis stages of all patients was as follows: grade 1 = 43 (12.7%), grade 2 = 109 (32.2%), grade 3 = 116 (34.2%) and grade 4 = 71 (20.9%); F0 = 12 (3.5%), F1 = 54 (15.9%), F2 = 100 (29.5%), F3 = 91 (26.8%) and F4 = 82 (24.2%).

M30 antigen levels in different stages of chronic HBV infection

We assessed serum

Discussion

In this study, we evaluated whether serum M30-antigen levels can serve as useful biomarkers of liver necroinflammation in the clinical spectrum of HBV infection. Serum M30 antigen levels were correlated with serum markers of liver inflammation and histologic inflammatory grades in patients with CHB. The mean level of M30-antigen in HBeAg negative CHB patients was significantly higher than that of inactive carriers. Furthermore, a combined analysis of AST and M30-antigen was able to detect

Funding

This work was supported by a grant from the Ministry of Health and Welfare, Republic of Korea (no. A102065).

Competing interests

We declare that we have no conflict of interests.

Ethical approval

The study protocols were approved by the Institutional Review Board of Human Research of Ajou University Hospital (AJIRB-MED-KSP-11-372) and the local research ethics committees at all participating hospitals. Informed consent to participate in the study was obtained from all study subjects.

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