Hyperammonemic encephalopathy: An unaccounted side effect of 5FU and capecitabine.

Abstract

e24108 Background: Metabolic encephalopathy is a serious but reversible condition that is characterized by a diffuse impairment of cognitive function due to the overabundance of various metabolites or toxins. Hyperammonemia ( > 80 μg/dL or > 47 μmol/L) is a well-known cause of metabolic encephalopathy and also a rare side effect of 5-Fluorouracil (5-FU) chemotherapy. Constipation and renal failure are two known risk factors for developing hyperammonemic encephalopathy with 5-FU use. Capecitabine is a 5-FU prodrug that is commonly used as a more tolerated and more convenient alternative chemotherapy agent. Despite being less common than with 5-FU, cases of hyperammonemic encephalopathy related to capecitabine use may be missed clinically due to under-testing. Additionally, diarrhea may be misinterpreted as a side effect of chemotherapy instead of an effective tool for identifying early disease and accelerating disease resolution. Methods: A search using Pubmed was conducted on January 4th, 2024 to identify cases of hyperammonemia and metabolic encephalopathy related to 5-Fluorouracil and capecitabine. The search strategy was ("metabolic encephalopathy 5-fluorouracil" OR “hyperammonemia 5-fluorouracil”) AND (“metabolic encephalopathy capecitabine” OR “hyperammonemia capecitabine”). Cases were then organized into a table where factors of the cases were stratified. Results: A total of 59 total cases were identified. Every case where 5-FU was used reported a serum ammonia level, while only 5 of the 9 cases (55.55%) where capecitabine was used reported a serum ammonia level. Additionally, only 9 cases (15.25%) reported bowel movement status with 1 patient presenting with diarrhea, and 5 with constipation. The most common methods for managing metabolic encephalopathy in these patients included: branched chain amino acids (66.10%), discontinuing/changing the chemotherapeutic agent (62.71%), lactulose (37.29%), intravenous hydration (32.20%), and hemodialysis/hemofiltration (13.56%). For the 52 cases that reported it, the average duration of symptoms post-treatment was 2.15 days. Conclusions: A goal in managing patients receiving 5-FU or capecitabine with hyperammonemic encephalopathy is the excretion of ammonia without causing dehydration. This management is seen with the use of lactulose to increase bowel movements in patients with decompensated liver cirrhosis. Of note, 5FU and capecitabine have been shown to cause diarrhea as a grade 3 and 4 adverse effect in 12.7% and 16.6% of patients, respectively. Thus it can be theorized that the diarrhea from 5FU/capecitabine may offset the development of hyperammonemia. This principle could potentially be expanded to benefit patients with a history of chronic constipation. The oversight of hyperammonemia from 5-FU and capecitabine use is both dangerous and diminishes the quality of life from patients who are not proactively treated to prevent encephalopathy.