title: Severe hepatocytotoxicity linked to denosumab.
abstract: Denosumab (Prolia, Amgen, Thousand Oaks, CA, USA) is a fully human antibody to the receptor activator of nuclear factor-KB ligand (RANKL). We present a case of submassive hepatic necrosis with evidence implicating cytokine induction resulting from an immune reaction to denosumab.
  
  
  
  A 72-year-old lady presented with elevated liver enzymes. One month previously, she received a s/c administration of 60 mg of denosumab. Viral hepatitis A, B and C and human herpes viruses 6-7 were negative as were routine autoimmune serology. Transaminases reached more than 50 x ULN, and gamma-glutamyl-transpeptidase (GGT) increased to more than 30 x ULN. Serum bilirubin reached 13.8 mg/dL. The serum albumin level decreased to 2.8 g/L. Prednisone (40 mg) and ursodeoxycholic acid (900 mg) were administered. The Naranjo Adverse Drug Reaction probability score was 6, consistent with a probable adverse drug reaction. A liver biopsy revealed sub-massive hepatic necrosis consistent with drug-induced liver injury (DILI). During steroid tapering, there was a slow decline in the levels of both the transaminases and the GGT, and a concomitant increase in the serum albumin. A month after stopping prednisone and ursodeoxycholic acid, there was an acute increase in the level of the transaminases and a decrease in the serum albumin. Steroid reintroduction resulted in normalization of the liver enzymes and synthetic capacity. A lymphocyte toxicity assay to denosumab was demonstrated a hypersensitivity reaction to denosumab resulting in 31% toxicity. The control patient showed no toxicity to denosumab. Cytokine levels (pg/mL) were as follows: Interleukin (IL)1 was 1193 (normal-24.5), IL8 357 (20-60), RANKL 224 (60-80), RANTES 215 (15-50), TNF-a 850 (25-50), TGF-b 546 (20-40), VEGF 735 (25-30). Serum RANKL was markedly reduced in the presence of denosumab (16 pg/mL). The elevated markers of apoptosis ccK18(M-30)(68-132) 140 IU and K18 apoptosis+ necrosis (M65) (62-213) 322 U/L implicate necrosis.
  
  
  
  We suggest that RANKL inhibition can produce severe hepatic necrosis together with an increase in proinflammatory cytokines.
authors.affiliation: Department of Internal Medicine C, Kaplan Medical Center, Rehovot, Israel, Affiliated to The Hebrew University, Hadassah, Jerusalem, Israel. stephen@malnick.net.
authors.forename: S
authors.initials: S
authors.lastname: Malnick
authors.forename: Y
authors.initials: Y
authors.lastname: Maor
authors.forename: E
authors.initials: E
authors.lastname: Melzer
authors.forename: N N
authors.initials: NN
authors.lastname: Ziv-Sokolowskaia
authors.forename: M G
authors.initials: MG
authors.lastname: Neuman
mesh_terms: D000368:Aged; D050071:Bone Density Conservation Agents / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury; D000069448:Denosumab / Q000009:adverse effects*; D005260:Female; D006801:Humans; D053245:RANK Ligand; D014409:Tumor Necrosis Factor-alpha
chemical_list: D050071:Bone Density Conservation Agents; D053245:RANK Ligand; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D000069448:Denosumab