Serum ceruloplasmin levels correlate negatively with liver fibrosis in males with chronic hepatitis B: a new noninvasive model for predicting liver fibrosis in HBV-related liver disease.

Da-Wu Zeng,Su Lin,Jing Dong,You-Bing Li,Jing Chen,Jia You,Qi Zheng,Yu-Rui Liu,Jia-Ji Jiang,Yue-Yong Zhu,Jie-Min Zhang,Anand S Mehta

doi:10.1371/journal.pone.0077942

Abstract

AimsThis study aimed to investigate associations between ceruloplasmin (CP) levels, inflammation grade and fibrosis stages in patients with chronic hepatitis B (CHB) and to establish a noninvasive model to predict cirrhosis.MethodsLiver biopsy samples and sera were collected from 198 CHB patients randomized into a training group (n=109) and a validation group (n=89). CP levels were determined using nephelometric immunoassays. Relationships between CP and liver inflammation and fibrosis were analyzed by Spearman rank correlation. Receiver operator characteristic (ROC) curves were used to evaluate the diagnostic value of CP for determining liver fibrosis in CHB. The liver pathology-predictive model was built using multivariate logistic regression analysis to identify relevant indicators.ResultsCP levels were lower in males than in females, lower in patients with inflammation stage G4 compared to other stages and lower in cirrhotic compared to non-cirrhotic patients. Using area under the curve (AUC) values, CP levels distinguished different stages of inflammation and fibrosis. Multivariate analysis showed that CP levels were all significantly associated with cirrhosis in males. A model was developed combining routine laboratory markers APPCI (alpha-fetoprotein [AFP], prothrombin time, and platelets [PLT] with CP) to predict fibrosis in CHB patients. The APPCI had a significantly greater AUC than FIB-4 (aspartate aminotransferase [AST]/ alanine aminotransferase [ALT]/PLT/age), APRI (AST/PLT ratio index), GPI (globin/PLT), and APGA (AST/PLT/gammaglutamyl transpeptidase [GGT]) models (all P-values<0.001).ConclusionsCP levels correlate negatively and indirectly with inflammation and fibrosis stages in male CHB patients. The APPCI model uses routine laboratory variables with CP to accurately predict liver fibrosis in CHB.

Highlights

The World Health Organization estimates that the hepatitis B virus (HBV) causes chronic infection in 350-400 million people worldwide, of whom 75% are Asian [1,2]
We investigated associations between serum CP levels and inflammation grade and liver fibrosis stages in patients with chronic hepatitis B-virus related liver disease
We showed that serum CP levels were negatively and indirectly correlated with inflammation and fibrosis stages in males

Summary

Introduction

The World Health Organization estimates that the hepatitis B virus (HBV) causes chronic infection in 350-400 million people worldwide, of whom 75% are Asian [1,2]. Most studies of model development have focused on noninvasive markers for evaluating patients with chronic hepatitis C, including FIB-4 (AST/ ALT/ PLT/age) [15], FibroTest (α-2-macroglobulin, γ-glutamyl transpeptidase [GGT], apolipoprotein, haptoglobin, total bilirubin, age and gender) [16], APRI (AST/PLT ratio) [17], European Liver Fibrosis (ELF) score (hyaluronate [HA], procollagen III amino terminal peptide, and tissue inhibitor of metalloproteinase 1 [TIMP-1], age) [18]; and Hepascore (bilirubin, GGT, hyaluronate, α-2-macrogluobulin, age and gender) [19]. The cost of certain methods, especially when performance requires specific equipment or non-routine laboratory tests, and the ease of measurement of predictive biomarkers are other factors that have been suggested to limit the use of some noninvasive models in some institutions [12,21,22,23], even though all are less expensive than liver biopsy

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