# C4d Immunoreactivity in Autoimmune and HBV-Induced Hepatitis: Implications for Complement-Mediated Hepatocellular Injury

## TL;DR

This study compares immune complex deposition in autoimmune and hepatitis B-induced liver disease, finding that complement activity correlates with liver inflammation and viral presence.

## Contribution

The study reveals a novel link between HBV activity and complement-mediated liver injury through C4d and HBsAg colocalization in CHB.

## Key findings

- C4d deposition was observed in 73.3% of AIH cases and 84.7% of CHB cases.
- C4d staining in CHB correlated with elevated ALT and liver inflammation.
- HBsAg and C4d signals colocalized in hepatocytes, suggesting a viral-complement interaction in CHB.

## Abstract

Background: Although immune complex formation is widely acknowledged as the etiological agent for the development of systemic lupus erythematosus, polyarteritis nodosa, reactive arthritis, etc., its roles in chronic hepatitis are less understood. This study aims to compare the immunohistochemistry profile of immune complex deposition in patients with chronic hepatitis B (CHB) and autoimmune hepatitis (AIH). Methods: Immunohistochemistry of C4d, a widely used marker for complement deposition was employed on liver biopsies from 72 and 15 patients with CHB and AIH, respectively. Statistical analysis was performed to analyze its prevalence and its association with a range of clinical and histological parameters. Results: Among the 15 AIH biopsies examined, C4d deposition was observed in 11 cases (73.3%), the majority of which showed a periportal staining pattern (10/11). In CHB, 61 (84.7%) of 72 cases tested positive for C4d, which did not differ significantly with that of AIH. While the periportal pattern was predominantly observed in CHB cases, positive staining in central veins, sinusoids, and hepatic parenchyma were also documented. In particular, C4d deposition is significantly associated with elevated serum ALT and liver inflammation in CHB. Of note, in specimens with a patchy parenchymal C4d staining pattern, a spatially correlated HBsAg IHC signal was observed in adjacent sections from the same tissue. Conclusions: These data suggest an involvement of immune complex-mediated immunopathy in autoimmune hepatitis and HBV-induced hepatitis. The positive intrahepatic C4d signal was associated with heightened liver inflammation. The colocalization of the C4d signal on hepatocytes with HBsAg strongly suggests a causal relationship between viral activity and complement deposition. These observations align with our recent evidence implicating the contribution of capsid–antibody complexes in the pathogenesis of CHB.