Severe Encephalopathy, Lactic Acidosis and Hyperammonaemia With FOLFIRI Plus Aflibercept After Two-stage Hepatectomy: A Case Report

Discussion

5-FU is an important component of first- and second-line chemotherapy regimens for metastatic CRC. The most common adverse events associated with 5-FU are gastrointestinal symptoms (nausea, vomiting, and diarrhoea) and bone marrow suppression (stomatitis, neutropenia, and thrombocytopaenia). There have been rare reports of lactic acidosis and hyperammonaemic encephalopathy due to administration of 5-FU (3-5). Although the underlying mechanisms of toxicity are unknown, three hypotheses have been proposed. The first suggests that hyperammonaemia occurs secondarily to ATP deficiency (5, 6). Ammonia is the final metabolite of 5-FU and is converted to urea through an adenosine triphosphate (ATP)-dependent cycle. However, the tricarboxylic acid cycle, which generates ATP, is inhibited by fluoroacetate, an intermediate catabolite of 5-FU. Thus, 5-FU-induced ATP deficiency leads to inhibition of ammonia metabolism, resulting in hyperammonaemia (5, 6). Inhibition of the tricarboxylic acid cycle also induces the metabolism of pyruvate to lactate, resulting in lactic acidosis. The second hypothesis proposes that a deficiency in dihydropyrimidine dehydrogenase, which is responsible for the degradation of 85% of 5-FU, leads to an increase in blood concentrations of 5-FU and its metabolite ammonia (7). In the third hypothesis, loss of appetite due to chemotherapy results in reduced thiamine uptake. 5-FU has also been reported to increase cellular thiamine metabolism. The resulting thiamine deficiency (beriberi) leads to lactic acidosis, Wernicke's encephalopathy, and peripheral neuropathy (4). In the patient described here, lactic acidosis and hyperammonaemia may have been caused by a combination of declining liver function after two-stage hepatectomy and decreased appetite and dehydration after chemotherapy. Although the patient could have been continued on 5-FU, we felt that the possibility of hyperammonaemia recurrence was too high. If she requires chemotherapy in the future, the treatment regimen will be changed to omit 5-FU.

In conclusion, encephalopathy, lactic acidosis, and hyperammonaemia are rare adverse events associated with 5-FU. To our knowledge, there have been no other reports of these events occurring after two-stage hepatectomy. Caution should be exercised when introducing 5-FU-based chemotherapy to patients who have received long-term chemotherapy and undergone extensive liver resection.