Distinct Biomarker Profiles of B-Cell Activation in Metabolic and Viral Hepatic Fibrosis

Increasing evidence underlines the role of B-cells in the development of hepatic fibrogenesis following viral infections and metabolic dysfunction, through different mechanisms depending on the etiology. Circulating biomarkers of B-cell activation-such as B-cell activating factor (BAFF), immunoglobulin G (IgG) subclasses, and free light chains (FLCs)-may be associated with different results between viral and metabolic hepatic fibrosis, supporting their use as diagnostic tools. We conducted a case-control study including 100 patients with liver fibrosis, 50/100 of metabolic etiology and 50/100 of viral etiology. A reference group of 30 healthy donors was included as control. Serum levels of BAFF were measured using ELISA, while IgG subclasses (IgG1, IgG2, IgG3, IgG4), κ-FLC, λ-FLC, and the κ/λ ratio were quantified by turbidimetric methods. In univariate analysis, κ-FLC, λ-FLC, and BAFF levels were significantly elevated in both patient groups, with the highest concentrations consistently observed in metabolic fibrosis. IgG2 was selectively increased in metabolic fibrosis, whereas IgG3 was specifically elevated in viral fibrosis. Multivariate analysis confirmed these findings, showing a clear clustering of the three groups and identifying increased BAFF and κ-FLC as key features of metabolic fibrosis, while elevated IgG3 emerged as the most distinctive marker of viral etiology. These results reveal distinct B-cell-related immunological signatures in metabolic and viral hepatic fibrosis supporting the role of BAFF, FLCs, and IgG subclasses as biomarkers of etiological differentiation, and provide novel insights into the immune mechanisms driving fibrosis progression, potentially contributing to the identification of new therapeutic targets.