Pazopanib-Induced Liver Injury: A Near TKO From a TKI

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A 56 year old man with Renal Cell Carcinoma on Pazopanib was admitted with right upper quadrant (RUQ) abdominal pain and fatigue. He had no significant alcohol use. Vitals were normal, exam revealed scleral icterus, jaundice, and mild RUQ tenderness. Labs were notable for Total bilirubin 4.1 mg/dL, AST 770 U/L, ALT 909 U/L, and ALP 681 U/L. Viral markers for Hepatitis A, B, C, E and Cytomegalovirus (CMV) and autoimmune panel were negative. Serum ceruloplasmin level was 30mg/dl, ferritin 2365ng/ml, and transferrin saturation 65%. Ultrasound with liver doppler was unremarkable. Liver biopsy revealed severe lobular inflammation and portal expansion by lymphocytes, with admixed plasma cells and eosinophils. Stains for fibrosis, iron deposition, and alpha-1 antitrypsin globules were negative. IHC staining was negative for CMV and HSV antigens. He was diagnosed with drug-induced liver injury (DILI) from Pazopanib and started on ursodiol with tapering course of oral prednisone. Liver enzymes gradually improved and completely resolved by week 10.Pazopanib, a Tyrosine Kinase Inhibitor (TKI), is approved for the treatment of Renal Cell Carcinoma (RCC) and Soft Tissue Sarcomas (STS). It targets VEGF receptor and other kinases involved in tumor angiogenesis. The mechanism of TKI induced liver injury remains unclear. Mitochondrial toxicity, inhibition of glycolysis, and apoptosis has been proposed to be the mechanisms of hepatotoxicity. In our case, patient had a score of 7 on the Naranjo probability scale for adverse drug reaction, indicating that Pazopanib is the probable cause of DILI. Although hepatotoxicity with Pazopanib has been reported, only a single case report with accompanying biopsy has been reported in the literature. Both patients in the report had normal baseline liver function tests and significant AST and ALT elevation by week 6 after initiation. Liver biopsies in these patients revealed similar features. With increasing use of TKI agents in oncotherapy, one must be aware of the potential adverse effect of DILI from newer agents such as Pazopanib. The onset of DILI from Pazopanib ranges from 4-12 weeks after initiation. Majority of patients recover completely on drug discontinuation with normalization of liver function and enzymes as seen in our patient, however occasional fatalities have been reported. Thus monitoring liver enzymes on TKI therapies is imperative for early recognition of Pazopanib induced DILI and prompt discontinuation of the drug.