Hyperammonemic encephalopathy during XELOX regimen. Is it capecitabine or oxaliplatin responsible?

Abstract

Hyperammonemic encephalopathy represents a rare adverse effect of several chemotherapeutic agents, occurring in about 0.7% of patients treated with fluoropyrimidines, and it is independent from dihydropyrimidine dehydrogenase deficiency. Instead, its physiopathology is linked to the inhibition of Krebs cycle by fluoroacetate, leading to decreased ATP production, and to the inhibition of the urea cycle. Oxaliplatin seems to induce hyperammonemic encephalopathy in a similar way, acting on mitochondria. Here, we report the intriguing case of acute hyperammonemic encephalopathy in a 65-year-old patient with preserved liver function, who was treated with oxaliplatin and capecitabine for a metastatic, G1, atypical lung carcinoid. We reviewed the literature and found very few reports of oxaliplatin or capecitabine-induced hyperammonemic encephalopathy. Out of five cases of capecitabine-related hyperammonemic encephalopathy analyzed (four plus our case), median time to hyperammonemic encephalopathy onset was 6 days, with median serum ammonia levels of 213 μmol/L. Oxaliplatin-related hyperammonemic encephalopathy analyzed cases were three (two plus ours), with a median time to hyperammonemic encephalopathy of 11 days and median serum ammonia levels of 167 μmol/L. Identified predisposing factors for chemotherapy-induced hyperammonemia, such as dehydration, liver and renal impairment, infections, and sarcopenia were absent in our case. We hypothesize that the combination of a platinum-derivative and a fluoropyrimidine multiplies the risk of hyperammonemic encephalopathy, even in the absence of predisposing factors nor impaired liver function. We therefore suggest to always consider the risk of hyperammonemia when starting fluoropyrimidines-based chemotherapy, especially combined with platinum-derivatives, and to timely investigate neurologic symptoms monitoring ammonia serum levels.

Case report: Uridine triacetate in the management of delayed onset 5-fluorouracil toxicity: A case report and review of literature

“…Frontiers in Pharmacology frontiersin.org Federico et al, 2020). However, these findings are not always present and were not evident in our patient.…”

“…Encephalopathy often follows acute cerebellar syndrome or posterior reversible encephalopathy syndrome (PRES) ( Dedić Plavetić et al, 2014 ). Findings of hyperammonemia on labs and diffuse periventricular white matter changes in the T2-weighted magnetic resonance imaging may be seen ( Choi et al, 2001 ; Di Federico et al, 2020 ). However, these findings are not always present and were not evident in our patient.…”

Severe Acute Liver Dysfunction Induces Delayed Hepatocyte Swelling and Cytoplasmic Vacuolization, and Delayed Cortical Neuronal Cell Death

“…After the diagnosis of hepatic encephalopathy, removal of toxic substances, mainly ammonia, and correction of metabolism of amino acids, etc., are performed from an early stage. Thus, although human patients rarely reach the high levels of ammonia described in this study, an increasing number of patients with various liver dysfunctions, including HE, was reported [ 59 , 60 , 61 , 62 , 63 , 64 ]. Patients often present with pathological conditions, such as liver cirrhosis, and it is thought that in vivo histopathological examination of the liver is necessary.…”