Severe hepatocytotoxicity linked to denosumab

Area of Science:

• Hepatology and Immunology
• Pharmacovigilance and Drug Safety

Background:

• Denosumab is a fully human monoclonal antibody targeting receptor activator of nuclear factor-κB ligand (RANKL), used in treating conditions like osteoporosis.
• Elevated liver enzymes and potential drug-induced liver injury (DILI) necessitate careful monitoring in patients receiving denosumab.

Observation:

• A 72-year-old female presented with acute liver injury (elevated transaminases, GGT, bilirubin; decreased albumin) one month post-denosumab administration.
• Exclusion of viral hepatitis and autoimmune markers, coupled with a positive Naranjo score and liver biopsy findings of sub-massive hepatic necrosis, indicated DILI.
• A lymphocyte toxicity assay confirmed a hypersensitivity reaction to denosumab, demonstrating 31% toxicity.

Findings:

• Treatment with prednisone and ursodeoxycholic acid initially improved liver function, but relapse occurred upon steroid withdrawal, necessitating reintroduction.
• Elevated pro-inflammatory cytokines (IL-1, IL-8, TNF-α, RANTES, TGF-β, VEGF) and markers of apoptosis/necrosis (ccK18, M65) were observed.
• Serum RANKL levels were significantly reduced by denosumab, as expected, but the immune response led to hepatic injury.

Implications:

• This case suggests that RANKL inhibition by denosumab can trigger severe hepatic necrosis through immune-mediated cytokine induction.
• The findings underscore the importance of considering denosumab as a potential cause of DILI, especially in cases of unexplained liver injury.
• Further research into the immunopathogenesis of denosumab-induced liver injury is warranted to refine risk assessment and management strategies.