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

Aims
This 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.
Methods
Liver 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.
Results
CP 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).
Conclusions
CP 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.

研究目的
本研究旨在探讨慢性乙型肝炎（chronic hepatitis B, CHB）患者血清铜蓝蛋白（ceruloplasmin, CP）水平、炎症分级与肝纤维化分期之间的关联，并构建无创模型以预测肝硬化。
方法
本研究纳入198例慢性乙型肝炎患者，采集其肝活检样本与血清标本，按随机分组原则分为训练组（n=109）与验证组（n=89）。采用散射比浊免疫法检测血清CP水平。通过Spearman秩相关分析（Spearman rank correlation）探讨CP与肝脏炎症、纤维化的相关性。采用受试者工作特征曲线（receiver operator characteristic, ROC）评估CP对慢性乙型肝炎患者肝纤维化的诊断价值。采用多因素logistic回归分析（multivariate logistic regression analysis）构建肝脏病理预测模型，筛选相关影响指标。
结果
男性患者的CP水平低于女性患者；炎症分期G4期患者的CP水平低于其他分期患者；肝硬化患者的CP水平低于非肝硬化患者。以曲线下面积（area under the curve, AUC）为评估指标，CP水平可区分不同程度的炎症与纤维化分期。多因素分析显示，男性患者的CP水平均与肝硬化显著相关。本研究构建了联合常规实验室指标APPCI（甲胎蛋白[alpha-fetoprotein, AFP]、凝血酶原时间、血小板[platelets, PLT]与CP）的模型，用于预测慢性乙型肝炎患者的肝纤维化。APPCI模型的曲线下面积显著高于FIB-4（天冬氨酸氨基转移酶[aspartate aminotransferase, AST]/丙氨酸氨基转移酶[alanine aminotransferase, ALT]/PLT/年龄）、APRI（AST/PLT比值指数）、GPI（球蛋白/PLT比值）及APGA（AST/PLT/γ-谷氨酰转移酶[gammaglutamyl transpeptidase, GGT]）模型（所有P值均<0.001）。
结论
男性慢性乙型肝炎患者的CP水平与炎症及纤维化分期呈负相关。本研究构建的APPCI模型联合常规实验室指标与CP，可准确预测慢性乙型肝炎患者的肝纤维化。