1Division of Pediatric Hematology/Oncology, Eskişehir Osmangazi University, Faculty of Medicine, Eskişehir, Turkey.
2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Faculty of Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey.
L-asparaginase is enzymatically active against glutamine, but with a significantly lower affinity against glutamine than L-asparagine . L-glutaminase activity results in a reduction in the plasma glutamine level . N-acetylcysteine (NAC) increases glutathione and antioxidant pools in hepatic cells, and thus increases the resistance of hepatic cell membranes . Here, we describe a pediatric patient who developed severe hepatotoxicity accompanied by hyperamylasemia, hyperlipidemia, and elevated transaminase and bilirubin levels following the administration of 5 doses of L-asparaginase, and the parameters that were resolved following NAC infusion.
In the 2.5-year-old patient who was being followed-up after a diagnosis of pre-B ALL, induction therapy was initiated with a combination chemotherapy regimen comprising 60 mg/m2 prednisolone (oral) (days 1–33), 1.5 mg/m2 vincristine and 30 mg/m2 daunorubicin (days 7, 15, 22, and 29), and 5,000 µ/m2 L-asparaginase (
Liver dysfunction is a significant problem in patients receiving chemotherapy or immunosuppressive agents for hematologic malignancies. The most common cause of liver disease is drug toxicity. Furthermore, viruses can cause liver dysfunction. Hepatitis B is the most common of these viral agents . Antibiotic therapy may lead to transient and mild transaminase elevation. Many drugs without antineoplastic effects such as allopurinol, ketoconazole, fluconazole, and ondansetron may cause hepatotoxicity but do not induce the fatty changes in the liver associated with steatosis . Other agents administered as a part of the combination chemotherapy regimen, including daunorubicin and vincristine, are uncommon hepatic toxins that are not known to produce fatty changes. Fatty liver is a relatively common finding induced by L-asparaginase toxicity .
L-asparaginase induced hepatotoxicity appears to be related to oxidative stress, glutamine deficiency, and decreased hepatic protein synthesis, and subsequent impairment of beta oxidation in mitochondria . As a result of the impaired mitochondrial beta oxidation, free fatty acids cannot be metabolized, and lactate and reactive oxygen radicals further increase and accumulate. The accumulated radicals lead to mitochondrial DNA damage, which results in disrupted aerobic metabolism in cells, and in turn lactic acidosis and triglyceride accumulation. The result is intracellular steatosis .
Glutathione is involved in the antioxidant defense mechanism against major reactive oxygen radicals. A small percentage (10–15%) of the total cell glutathione is present in the mitochondria. Despite this, mitochondrial glutathione plays a critical role in the maintenance of mitochondrial functions and in sustaining cell viability . NAC is a glutathione precursor and acts by direct degradation of free oxygen radicals . Previous studies have reported that NAC reduces lipid peroxidation and moderates the reduction in hepatic glutathione in non-alcoholic steatohepatitis patients . A study conducted by Baumgardner et al.  demonstrated that NAC is an effective hepatic antioxidant that eliminates the lipid peroxidation induced by non-alcoholic steatohepatitis, increases the reduction of hepatic glutathione, inhibits TNF-alpha production, and reduces inflammation, thereby significantly reducing hepatocyte damage.
Glutathione is an important intracellular antioxidant, which may be negatively affected by the reduction in glutamine levels that occurs as a result of L-asparaginase-associated inhibition of protein synthesis and L-glutaminase activity. In contrast, chemotherapeutics lead to increased oxidative stress and depletion of glutathione levels. The depletion and impaired synthesis of glutathione both result in a reduction in the glutathione pool. A study on mice demonstrated that in L-asparaginase-induced pancreatitis, glutathione levels were lower, and malondialdehyde, glucose, and triglyceride levels were higher in the group receiving asparaginase than in the control group and in the group receiving asparaginase concurrently with carnitine. Additionally, it was reported that in the group given asparaginase concurrently with carnitine, the glutathione, malondialdehyde, glucose, triglyceride, and amylase levels were closer to those of the control group than to those of the group receiving asparaginase .
Our patient's fasting triglyceride and cholesterol levels normalized, while the transaminase level showed a slight, temporary increase during reinduction chemotherapy with