
Hyperammonemia after capecitabine associated with occult impairment of the urea cycle
Author(s) -
Chu Gilbert,
Salzman Julia
Publication year - 2019
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.2036
Subject(s) - hyperammonemia , urea cycle , medicine , endocrinology , biology , genetics , amino acid , arginine
Background Cancer patients receiving chemotherapy often complain of “chemobrain” or cognitive impairment, but mechanisms remain elusive. Methods A patient with gastric cancer developed delirium and hyperammonemia after chemotherapy with the 5‐fluorouracil pro‐drug capecitabine. Exome sequencing facilitated a search for mutations among 43 genes associated with hyperammonemia and affecting the urea cycle directly or indirectly. Results The patient's urea cycle was impaired by capecitabine‐induced liver steatosis, and portosystemic shunting of gut ammonia into the systemic circulation. The patient was also heterozygous for amino acid substitution mutations previously reported to create dysfunctional proteins in 2 genes, ORNT2 (ornithine transporter‐2 for the urea cycle), and ETFA (electron transport flavoprotein alpha for fatty acid oxidation). The mutations explained the patient's abnormal plasma amino acid profile and exaggerated response to allopurinol challenge. Global population variations among the 43 hyperammonemia genes were assessed for inactivating mutations, and for amino acid substitutions predicted to be deleterious by complementary algorithms, SIFT and PolyPhen‐2. One or 2 deleterious mutations occur among the 43 genes in 13.9% and 1% of individuals, respectively. Conclusions Capecitabine and 5‐fluorouracil inhibit pyrimidine biosynthesis, decreasing ammonia utilization. These drugs can induce hyperammonemia in susceptible individuals. The risk factors of hyperammonemia, gene mutations and liver dysfunction, are not rare. Diagnosis will trigger appropriate treatment and ameliorate brain toxicity.