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Is N-acetylcysteine infusion an effective treatment option in L-asparaginase associated hepatotoxicity?

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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... 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/m prednisolone (oral) (days 1–33), 1.5 mg/m vincristine and 30 mg/m daunorubicin (days 7, 15, 22, and 29), and 5,000 µ/m L-asparaginase (E... NAC therapy was re-started at an oral dose of 10 mg/kg daily and after the sixth day of NAC therapy, serum transaminase levels decreased to ALT 172 IU/L, AST 53 IU/L, and ALP 104 IU/L... 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... 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.

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Therapeutic agents used and changes in AST, ALT and ALP.Abbreviations: ALT, alanine transaminase; ALP, alkaline phosphatase; AST, aspartate transaminase; L-Asp, L-asparaginase; NAC, N-acetylcysteine.
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Figure 2: Therapeutic agents used and changes in AST, ALT and ALP.Abbreviations: ALT, alanine transaminase; ALP, alkaline phosphatase; AST, aspartate transaminase; L-Asp, L-asparaginase; NAC, N-acetylcysteine.

Mentions: 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 (E. Coli-Asp) (8 doses) (days 12, 15, 18, 21, 24, 27, 30, and 33). After the fifth L-asparaginase administration, the patient's laboratory results were as follows: alanine transaminase (ALT) 501 IU/L, aspartate transaminase (AST) 664 IU/L, gamma-glutamyl transferase (GGT) 1,297 IU/L, alkaline phosphatase (ALP) 246 IU/L, total/direct bilirubin 7/6.09 mg/dL, total cholesterol 272 mg/dL, triglyceride 571 mg/dL, and amylase 146 IU/L. The patient's clinical findings rapidly deteriorated, and abdominal distention and hepatomegaly were observed. Oral feeding was discontinued, and antibiotic (carbapenem and teicoplanin) and antifungal therapy (liposomal amphotericin B) was initiated. Tests for hepatitis A, B, and C, cytomegalovirus, Epstein Barr virus, parvovirus, and human immunodeficiency virus serology returned negative results. There was no growth in blood cultures. Abdominal computerized tomography revealed an increased liver size and density due to hepatosteatosis (Fig. 1). Drug-related toxic hepatitis was considered because of the progressively increased serum transaminase, bilirubin, amylase, and triglyceride levels. Liver biopsy could not be performed. The sixth dose of L-asparaginase was omitted. The NAC was started at a dose of 150 mg/kg for the first hour, 50 mg/kg for a subsequent 4 hours, and 100 mg/kg for the remaining 16 hours. Our patient received NAC infusion at a dose of 100 mg/kg/day over 4 days. The seventh administered dose of L-asparaginase was reduced by 50%. However, on day 2 of therapy, serum ALT was 689 IU/L, AST was 397 IU/L, and ALP was 302 IU/L. NAC therapy was re-started at an oral dose of 10 mg/kg daily and after the sixth day of NAC therapy, serum transaminase levels decreased to ALT 172 IU/L, AST 53 IU/L, and ALP 104 IU/L. After completion of induction chemotherapy, fasting cholesterol and triglyceride levels turned to normal. The administered therapies and changes in transaminase and bilirubin levels for induction chemotherapy are shown in Fig. 2. Hepatotoxicity was not observed during consolidation therapy, which consisted of high dose methotrexate. Consolidation followed a reinduction protocol, and Erwinia asparaginase was administered instead of E. Coli asparaginase. Although this protocol also used the same dose of vincristine and steroids as the induction protocol, hypertriglyceridemia was not observed. There was a temporary mild elevation of transaminases.


Is N-acetylcysteine infusion an effective treatment option in L-asparaginase associated hepatotoxicity?
Therapeutic agents used and changes in AST, ALT and ALP.Abbreviations: ALT, alanine transaminase; ALP, alkaline phosphatase; AST, aspartate transaminase; L-Asp, L-asparaginase; NAC, N-acetylcysteine.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5383593&req=5

Figure 2: Therapeutic agents used and changes in AST, ALT and ALP.Abbreviations: ALT, alanine transaminase; ALP, alkaline phosphatase; AST, aspartate transaminase; L-Asp, L-asparaginase; NAC, N-acetylcysteine.
Mentions: 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 (E. Coli-Asp) (8 doses) (days 12, 15, 18, 21, 24, 27, 30, and 33). After the fifth L-asparaginase administration, the patient's laboratory results were as follows: alanine transaminase (ALT) 501 IU/L, aspartate transaminase (AST) 664 IU/L, gamma-glutamyl transferase (GGT) 1,297 IU/L, alkaline phosphatase (ALP) 246 IU/L, total/direct bilirubin 7/6.09 mg/dL, total cholesterol 272 mg/dL, triglyceride 571 mg/dL, and amylase 146 IU/L. The patient's clinical findings rapidly deteriorated, and abdominal distention and hepatomegaly were observed. Oral feeding was discontinued, and antibiotic (carbapenem and teicoplanin) and antifungal therapy (liposomal amphotericin B) was initiated. Tests for hepatitis A, B, and C, cytomegalovirus, Epstein Barr virus, parvovirus, and human immunodeficiency virus serology returned negative results. There was no growth in blood cultures. Abdominal computerized tomography revealed an increased liver size and density due to hepatosteatosis (Fig. 1). Drug-related toxic hepatitis was considered because of the progressively increased serum transaminase, bilirubin, amylase, and triglyceride levels. Liver biopsy could not be performed. The sixth dose of L-asparaginase was omitted. The NAC was started at a dose of 150 mg/kg for the first hour, 50 mg/kg for a subsequent 4 hours, and 100 mg/kg for the remaining 16 hours. Our patient received NAC infusion at a dose of 100 mg/kg/day over 4 days. The seventh administered dose of L-asparaginase was reduced by 50%. However, on day 2 of therapy, serum ALT was 689 IU/L, AST was 397 IU/L, and ALP was 302 IU/L. NAC therapy was re-started at an oral dose of 10 mg/kg daily and after the sixth day of NAC therapy, serum transaminase levels decreased to ALT 172 IU/L, AST 53 IU/L, and ALP 104 IU/L. After completion of induction chemotherapy, fasting cholesterol and triglyceride levels turned to normal. The administered therapies and changes in transaminase and bilirubin levels for induction chemotherapy are shown in Fig. 2. Hepatotoxicity was not observed during consolidation therapy, which consisted of high dose methotrexate. Consolidation followed a reinduction protocol, and Erwinia asparaginase was administered instead of E. Coli asparaginase. Although this protocol also used the same dose of vincristine and steroids as the induction protocol, hypertriglyceridemia was not observed. There was a temporary mild elevation of transaminases.

View Article: PubMed Central - PubMed

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

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... 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/m prednisolone (oral) (days 1–33), 1.5 mg/m vincristine and 30 mg/m daunorubicin (days 7, 15, 22, and 29), and 5,000 µ/m L-asparaginase (E... NAC therapy was re-started at an oral dose of 10 mg/kg daily and after the sixth day of NAC therapy, serum transaminase levels decreased to ALT 172 IU/L, AST 53 IU/L, and ALP 104 IU/L... 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... 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.

No MeSH data available.