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

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.

Ceruloplasmin, a reliable marker of fibrosis in chronic hepatitis B virus patients with normal or minimally raised alanine aminotransferase

“…We previously developed a new non-invasive model of APPCI to predict liver cirrhosis in CHB patients presenting different ALT levels and found that serum CP was a new marker, negatively correlated with liver fibrosis[25]. In the present study, we extended these results to CHB carriers with normal or minimally raised ALT.…”

“…Whether they are also applicable to CHB patients, however, is yet to be demonstrated. Therefore, new non-invasive models were recently developed to detect liver fibrosis in patients with CHB[19,25,45,46]. Compared with FIB-4 and GP, our CG model showed much greater AUC than FIB-4 to the GP model.…”

“…Non-invasive predictive models of fibrosis are therefore needed. Single markers have been proposed such as platelet count, AST and ALT, gamma-globulins, serum HBsAg levels, CP, red blood cell distribution width, Interleukin-2R, TGF-α, serum Golgi protein 73 (GP73), and miR-122[13,14,16,17,25,28-31]. However, currently, none of these markers are sufficiently liver-specific enough to accurately reflect fibrosis.…”

“…CP, which is an acute phase protein mostly synthesized in the liver, has been proposed to assess ballooning, steatosis, and inflammation in patients with liver fibrosis that are CHB carriers and afflicted by NASH[25,26]. We previously developed a new non-invasive model of APPCI to predict liver cirrhosis in CHB patients presenting different ALT levels and found that serum CP was a new marker, negatively correlated with liver fibrosis[25].…”

“…However, little is known of its relationship with liver fibrosis. Zeng et al[25] found that serum CP levels were negatively related to hepatic histological stage, and could be used to predict liver fibrosis in CHB-related liver disease. Nobili et al[26] showed that CP was associated with the odds of nonalcoholic steatohepatitis (NASH), inflammation, steatosis, and ballooning but not with fibrosis.…”