Case Presentation: A 69-year-old woman with a past medical history of metastatic ovarian cancer receiving treatment with crizotinib for 4 weeks presented to the hospital with weakness, lightheadedness, and hypotension. She denied any abdominal pain, nausea, vomiting, diarrhea, dysuria, or acetaminophen use. Physical exam revealed a blood pressure of 91/46, temperature 36.4 C, heart rate 58 beats per minute, oxygen saturation 96%, and no abnormalities on abdominal exam. Labs were pertinent for hemoglobin 11.7 g/dL (12.0-15.5), WBC 6.3 x 10(9) (3.5-10.5), platelets 238 x 10(9) (150-450), creatinine 0.8 mg/dL, total bilirubin 4.0 mg/dL (<1.2), direct bilirubin 2.5 mg/dL (0-0.3), lactate 3.3 mmol/L, alkaline phosphatase 233 u/L (55-142), alanine aminotransferase 4,146 u/L (7-45), and aspartate aminotransferase 3,373 u/L (8-43). Her liver function tests were normal prior to starting crizotinib. MRI abdomen demonstrated heterogeneous hepatic enhancement without biliary ductal enlargement. She was admitted to the hospitalist team for management of acute hepatitis. Crizotinib was held, normal saline was infused, and hepatology was consulted. Despite supportive measures her liver function continued to deteriorate resulting in fulminant liver failure and encephalopathy prompting ICU admission, intubation, and vasopressor support. The patient failed to improve which prompted withdrawal of care as per the family’s request.
Discussion: Crizotinib is a selective tyrosine kinase receptor inhibitor (TKI) approved by the FDA for treatment of advanced non-small cell lung cancer, however recent trials have shown promise in the treatment of ovarian cancer. The full mechanism is still unknown but likely related to the inhibition of anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1) and c-MET. Phase III clinical trials of crizotinib in patients with non-small cell lung cancer showed up to 57 % of patients developed elevation in aminotransferases, and up to 6 % developed a greater than 5 times increase in ALT, and AST. Thus, strict monitoring of liver function weekly during the first two months of treatment, and monthly thereafter is recommended. Withdrawal of crizotinib and standard hepatic failure treatment regimens are the only current treatment options for liver injury at this time.
Conclusions: Crizotinib and other emerging TKIs have shown promise for alternative oncologic treatment options, but there have been several cases of fatal liver failure reported. This is one of the first cases of fulminant liver failure in a patient treated with crizotinib for recurrent ovarian cancer. There is great need to address the mechanism of liver injury in these patients and identify those who may have an increased predisposition to the development of liver injury. As hospitalists are often first line providers for patients with acute liver injury it is important they consider and identify these medications as a cause of liver failure.