Novel Use of N-Acetylcysteine in Management of Tyrosine Kinase Inhibitor Induced Acute Liver Injury

Abstract

Tyrosine kinase inhibitors (TKIs) have been adopted in the treatment of a variety of malignancies. Despite their popularity, the underlying mechanism of the adverse effects seen with the use of TKIs is not completely understood. Acute liver injury is a known side effect of many of these drugs. Some papers have demonstrated that N-acetylcysteine may have a role in non-acetaminophen induced acute liver failure (NAI-ALF). There is little evidence supporting the use of N-acetylcysteine in the treatment of tyrosine kinase inhibitor-induced acute liver injury. This case report adds to the limited body of existing knowledge.We present a 67-year-old Caucasian female with a past medical history of anxiety, hyperlipidemia, in utero exposure to diethylstilbestrol (DES), and well-differentiated angiosarcoma of the right breast. She achieved remission for approximately six years after mastectomy with adjuvant chemotherapy and radiation. Subsequent surveillance imaging revealed new hepatic and cervical lesions. Further investigation with cutaneous biopsy near the occipital region confirmed recurrent metastatic angiosarcoma. The patient was started on high-dose pazopanib and initially tolerated the TKI without any adverse effects. However, after approximately two weeks of therapy, she began to experience dark colored urine, myalgias, and fatigue. These symptoms, along with significant elevations in liver enzymes (alanine transaminase of 1377 units/L, aspartate transaminase of 1212 units/L), prompted admission for evaluation of acute liver injury. The etiology of the acute liver injury was suspected to be secondary to TKI therapy. Treatment with intravenous N-acetylcysteine was initiated for non-acetaminophen induced acute liver failure (NAI-ALF) and resulted in a dramatic improvement in transaminases before discharge.Evidence suggests that there is a beneficial role for N-acetylcysteine in the management of NAI-ALF. However, when it comes specifically to the management of TKI induced acute liver injury, there is limited evidence to support its use. This case report highlights a possible use of N-acetylcysteine in the management of TKI mediated acute liver injury. Additional studies should be conducted to determine the role N-acetylcysteine plays in the management of TKI mediated liver injury.

Severe tyrosine-kinase inhibitor induced liver injury in metastatic renal cell carcinoma patients: two case reports assessed for causality using the updated RUCAM and review of the literature

“…Meta-analysis indicated safety and limited benefit regarding prolongation of patient survival with native liver without transplantation and survival after transplantation however, with no improvement of overall survival [70] NAC significantly reduces the level of reactive oxygen species produced by sunitinib and crizotinib and reduces sunitinib-and crizotinib-induced mitochondrial apoptosis and cellular damage. The use of NAC has been reported in several case reports of fulminant acute liver failure associated with TKIs [17,[71][72][73].…”

Pharmacotherapies for Drug-Induced Liver Injury: A Current Literature Review

“…In another study NAC together with prednisolone when used in cases of severe idiosyncratic DILI due to fupirtine (central acting non-opiod analgesic) showed a significant improvement in ALT, AST and INR within 2 weeks compared to those who were not treated with NAC ( Borlak et al, 2018 ). Furthermore, it is reported that NAC is benefit for tyrosine kinase inhibitors and norfloxacin-induced acute liver injury ( Elliott et al, 2016 ; Patel et al, 2019 ). As shown in a prospective controlled study by an American ALF research group, which was conducted in 24 medical centers for 8 years in 173 patients with ALF caused by non-APAP agents, NAC could improve the survival rate of patients who were at the early stage of DILI-related ALF and had not undergone liver transplantation ( Lee et al, 2009 ).…”

<p>Repurposing of N-Acetylcysteine for the Treatment of Dengue Virus-Induced Acute Liver Failure</p>

“…14 In general, these effects show NAC may be a useful agent to preserve liver function in patients with biliary obstruction, which was the path for glutathione production. 15…”