A case report of hyperammonemic encephalopathy induced by high-dose continuous infusion of 5-fluorouracil in a patient with rectal cancer

Introduction

Rectal cancer is the third most diagnosed cancer in the world and the second leading cause of cancer-related death after lung cancer (1), with a 5-year mortality rate of 86.6% for metastatic rectal cancer, according to the World Health Organization. Chemotherapy still plays an important role in the treatment of metastatic patients. 5-fluorouracil (5-FU), also known as 5-FU, is a commonly used chemotherapy drug for the disease, and its common adverse reactions included bone marrow suppression, gastrointestinal reactions, and occasionally oral mucositis, cerebellar ataxia, while long-term use can cause neurotoxicity. However, there are very few reports of hyperammonemia caused by 5-FU in domestic and foreign literatures.

5-FU-induced encephalopathy was reported in 1994 due to continuous infusion of high-dose 5-FU (2,600 mg/m² per week, continuous infusion for 48 hours) in other countries. Studies have shown that the proportion of high-dose continuous infusion of 5-FU leading to elevated blood ammonia is 5.7% (16/280) (2,3). Liaw et al. (4) reported 32 episodes of hyperammonemic encephalopathy and their clinical characteristics in 29 cancer patients between 1986 and 1998. The onset of related symptoms occurred on an average of 2.6±1.3 days after continuous infusion of 5-FU [400 mg/m² intravenous (IV) on day 1 + 1,200 mg/m²/d continuous infusion for 48 hours, every 2 weeks]. The average blood ammonia concentration was 347.78±239.44 µmol/L, which usually returned to normal levels within 48 hours. Other retrospective studies showed that some patients developed hyperammonemic encephalopathy even with low-dose 5-FU (4) or oral capecitabine (5).

Hyperammonemia encephalopathy is a neurological disease, and as the main nitrogenous product of protein catabolism, accumulated ammonia ions are harmful to the brain. When the blood ammonia concentration is 1.5 times higher than the upper limit of the normal laboratory range, clinical symptoms may occur including progressive drowsiness, confusion, weakness, ataxia (6), agitation, seizures, numbness, coma, and death (7). Meanwhile, the duration of hyperammonemia is associated with neurological abnormalities and impaired cognitive function (8,9). Ammonia capture agents (alternative pathway therapy), sodium phenylacetate and sodium benzoate for intravenous use or sodium phenylbutyrate for oral use work by trapping ammonia and converting it into compounds that are excreted in the urine. Since the clinical condition of hyperammonemia encephalopathy can deteriorate rapidly, it is also important to monitor respiratory status and intracranial pressure, as well as routine fluid rehydration and other treatments (10). Despite prompt treatment, many severe cases will still be fatal. Early recognition and aggressive treatment may provide opportunities for more favorable outcomes before irreversible brain damage develops.

In the present case, the patient developed hyperammonemic encephalopathy due to continuous infusion of high-dose 5-FU. Therefore, we analyzed the symptoms, signs, laboratory tests and other data of patients during chemotherapy, to provide reference for the prevention and treatment of hyperammonia-induced encephalopathy. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-23-167/rc).

Case presentation

The patient (67-year-old, male, case number 20200*****) was diagnosed as rectal cancer after undergoing colonoscopy due to rectal bleeding in May 2018. The pathology report of biopsy tissue indicated moderately differentiated adenocarcinoma (6 cm from the anal verge), with multiple lung metastases observed in the chest computed tomography (CT). Therefore, the clinical stage was determined to be T4N1M1 according to the 2018 National Comprehensive Cancer Network (NCCN) guidelines for colorectal cancer. The patient underwent three cycles of XELOX chemotherapy at another hospital from June to July 2018. In August 2018, he underwent surgical resection of rectal cancer via laparotomy. Postoperative immunohistochemistry results showed CD31 (vascular +), CK20 (+), CK7 (−), D2-40 (lymphatic vessel +), ERCC1 (−), GST-π (+), Ki-67 (approximately 10% +), MLH1 (+), MSH2 (+), MSH6 (+), Mucin-2 (+), P-gp (+), PMS2 (+), Topo-II (sporadic +) and Villin (+). Post-surgical diagnosis was rectal adenocarcinoma and lung metastasis (pT4N3M1a, stage IV). Thereafter, the patient underwent 10 cycles of targeted therapy with Avastin and XELOX chemotherapy. The treatment was evaluated as stable disease (SD) response according to the Response Evaluation Criteria in Solid Tumors (RECIST). From September 6, 2019, to December 19, 2019, the patient received maintenance chemotherapy with Xeloda 1,500 mg bid for 2 weeks and Avastin 500 mg on day 1. From January to May 2020, due to progressive enlargement of lung metastases, disease progression was considered according to the 2020 NCCN guidelines for the diagnosis and treatment of colorectal cancer. The patient received FOLFIRI chemotherapy (detailed dosage listed in Table 1) combined with Avastin (300 mg/kg intravenous infusion every three weeks). The FOLFIRI regimen consisted of irinotecan (Jiangsu Hengrui, National Medical Products Administration approval number H20020687) 130 mg/m² on day 1 + calcium folinate (Jiangsu Hengrui, National Medical Products Administration approval number H32022390) 400 mg/m² on day 1 + 5-FU (Tianjin Jinyao, National Medical Products Administration approval number H12020959) 400 mg/m² intravenous infusion on day 1 + 5-FU 1,200 mg/m² continuous infusion for 48 hours, every 3 weeks. During the fourth and fifth cycles of chemotherapy in 2020, the patient exhibited a significant increase in blood ammonia levels and corresponding symptoms of encephalopathy. The clinical diagnosis was hyperammonemic encephalopathy. Specific presentation was as follows.

• During the fourth cycle of chemotherapy, from 16:30 on March 18, 2020 to 17:00 on March 20, 2020, the patient received continuous intravenous infusion of 5-FU (2 mL/h). The patient developed sluggishness and a significant decrease in appetite from 07:30 on March, which progressed to serious changes at 18:30 on the same day, such as unconsciousness, unresponsiveness, with stiff limbs and no diarrhea. The 5-FU infusion pump had already completed simultaneously. Physical examination showed dilated pupils with a diameter of about 8 mm, sluggish pupillary light reflex, and increased muscle tone in all limbs. Electrocardiogram monitoring showed blood pressure of 150/85 mmHg, heart rate of 92 beats/min, and blood oxygen saturation of 96%. Rapid fingertip blood glucose was 9.5 mmol/L. Emergency tests showed red blood cells 4.18×10¹²/L, hemoglobin 129 g/L; blood urea nitrogen 10.7 mmol/L, blood ammonia 117.0 µmol/L, lactate 9.1 mmol/L, alanine aminotransferase 19 U/L; myoglobin 21 ng/mL. Emergency head CT scan showed age-related brain changes, without clear metastases. The clinical diagnosis was hyperammonemic encephalopathy of unknown cause. Treatment at that time included intravenous infusion of aspartate, ornithine injection 60 mL and oral lactulose to promote ammonia excretion after the patient regained consciousness. At 07:30 on March 21, the patient’s consciousness returned to normal, with appropriate responses and flexible limb movements. Ammonia was found to be <9 µmol/L on March 21. Subsequent examinations including ultrasound of the portal vein system and liver did not reveal any significant abnormalities. On March 24, the patient refused further examination and requested discharge (a consent form for refusing further examination and automatic discharge was signed).
• During the fifth treatment cycle from 16:30 on May 11 to 05:30 on May 13, the patient received continuous intravenous infusion of 5-FU (2 mL/h). On May 12, the patient began to experience an increase in bowel movements, with more than 10 loose stools that day, but did not visit the doctor. At 05:30 on May 13, the patient became unconscious, unresponsive to stimuli and developed stiff limbs. Physical examination showed no abnormalities in heart and lung auscultation, dilated pupils with a diameter of about 8 mm, sluggish pupillary light reflex, and increased muscle tone in all limbs. The 5-FU infusion pump had 22 mL of liquid left. Electrocardiogram monitoring showed blood pressure of 149/82 mmHg, heart rate of 85 beats/min, and blood oxygen saturation of 98%. Rapid fingertip blood glucose was 8.6 mmol/L. Emergency tests showed no abnormalities in blood routine and coagulation function. Blood urea nitrogen was 8.4 mmol/L, blood ammonia was 349.0 µmol/L, and lactate was 7.6 mmol/L. There were no symptoms of dizziness or vomiting before this chemotherapy. Since the emergency head CT scan from March 2020 showed age-related brain changes without clear evidence of metastases, brain metastases was not considered. However, in emergency situations, head CT scans may be temporarily postponed. The clinical diagnosis at this time was hyperammonemic encephalopathy (not excluding 5-FU-induced). Treatment: we immediately suspended the infusion of 5-FU, replaced it with 60 mL of aspartate and ornithine injection intravenously, and performed a vinegar enema. The patient’s consciousness gradually improved. At 18:30 on May 14, the patient returned to normal with appropriate responses, and the level of ammonia declined to normal (<9 µmol/L). All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal. The patient experienced severe consciousness disorders during two cycles of 5-FU chemotherapy, and was clinically diagnosed with hyperammonemic encephalopathy, which was considered to be highly correlated with the continuous infusion of high-dose 5-FU. The patient’s body surface area (BSA) and drug dosage during five cycles of FOLFIRI chemotherapy are shown in Table 1. The time of onset, symptoms, and recovery time of hyperammonemia during the fourth and fifth cycles of FOLFIRI chemotherapy are presented in Table 2. Timeline of the case presentation had been showed in Figure 1.

Figure 1 Timeline of the case presentation during the fourth and fifth cycle. 5-FU, 5-fluorouracil.

Discussion

The dose and cumulative effects of 5-FU are closely related to hyperammoniac encephalopathy

During the last two cycles of infusion of 5-FU, the patient suffered a transient and sharp increase in ammonia, encephalopathy, and significant gastrointestinal reactions. Other drugs used during chemotherapy included intravenous injection of esomeprazole and magnesium isoglycyrrhizinate, oral gabapentin, hydrocortisone sustained-release tablets, and celecoxib. The adverse drug reaction causality assessment, as per the evaluation method of Karch and Lasagna (11) in the 2012 Chinese version of the “Handbook of Adverse Drug Reaction Reporting and Monitoring Work” (12), is categorized into six levels. Based on this assessment, the hyperammonemic encephalopathy observed in this case was deemed to be “definitely” related to 5-FU. The reasons for the assessment were as follows: (I) there was a clear temporal relationship between the injection of 5-FU and the onset of patient’s symptoms; (II) after discontinuing 5-FU, the symptoms including consciousness and muscle rigidity improved, as well as the levels of ammonia and lactate; (III) the symptoms recurred after the second infusion of 5-FU and improved again after stopping the drug; (IV) recent clinical cases have reported a relationship between increased levels of ammonia and lactate with the occurrence of encephalopathy caused by 5-FU (2,13-15), which is consistent with known adverse reactions; (V) the symptoms observed in this patient were difficult to explain by other administered drugs or disease conditions.

In this case, the patient was treated for 17 months with xyloxase, an oral drug that is relatively non-cytotoxic in vitro. It is converted into 5-FU by the action of enzymes in the body to play its therapeutic role. Subsequently, intravenous high dose 5-FU treatment resulted in the occurrence of hyperammoniac encephalopathy. Both belong to the same class of chemotherapeutic drugs. Long-term use of 5-FU has dose accumulation effect, which may be the cause of hyperammonemia encephalopathy, which needs further investigation.

Pathogenic mechanisms of hyperammoniac encephalopathy induced by 5-FU

Brain magnetic resonance imaging (MRI) results may explain the manifestation of this type of encephalopathy and can be considered as an indicator of central nervous system toxicity caused by 5-FU (16). Most clinical reports of this type of neurotoxicity are delayed, and MRI suggests subacute multifocal leukoencephalopathy, which often occurs when 5-FU is combined with levomisole (17). Some scholars performed autopsies on patients who died of hyperammonemic encephalopathy caused by 5-FU combined with oxaliplatin. MRI showed diffuse brain edema in the bilateral cingulate cortex, while microscopic examination showed spongiform changes in the nervous tissue, increased astrocytosis in the subarachnoid and perivascular regions (perivascular astrocytosis). Clinically, it can manifest as type II dementia (18). However, this type of brain cortex lesion has not been widely confirmed in such patients.

The reason for encephalopathy is unclear. Yeh and Cheng (19) proposed two possible mechanisms: deficiency of DPD and the influence of 5-FU metabolites. (I) Approximately 2.7% of patients have been detected with DPD deficiency (20). DPD is the rate-limiting enzyme for 5-FU metabolism in the body, and is mainly distributed in the liver and peripheral blood lymphocytes. After 5-FU enters the blood, about 80% is metabolized and degraded into fluoroacetic acid through the DPD pathway, and the latter is further metabolized into fluoroacetate, with ammonia as the final product. DPD deficiency leads to the accumulation of 5-FU in the patient’s body (without elevated blood ammonia), and high concentrations of 5-FU can penetrate the cerebrospinal fluid, causing acute myelin sheath degeneration in neurons (19), finally leading to severe neurotoxicity and significant toxic side effects such as gastrointestinal reactions and bone marrow suppression (21). However, DPD deficiency cannot fully explain 5-FU-induced encephalopathy. (II) Fluoroacetate-induced encephalopathy is another possible pathogenic mechanism (22). It is suggested that the number or function of mitochondria is affected (3,23), and the stability of the tricarboxylic acid cycle can be disrupted when patients have concurrent factors such as renal insufficiency, infection, or muscle loss (24,25). Fluoroacetate, as a tricarboxylic acid cycle inhibitor, inhibits the tricarboxylic acid cycle, leading to insufficient adenosine triphosphate (ATP) synthesis, which in turn causes a disturbance in the ATP-dependent urea cycle, resulting in the inability to convert ammonia, accumulation of blood ammonia in the brain, followed by increased intracranial pressure with cellular edema, finally leading to encephalopathy (Figure 2) (26).

Figure 2 Transient accumulation of 5-FU catabolites and ammonia in the presence of various factors (26). 5-FU, 5-fluorouracil.

The correlation between reversible hyperammonemia, senile brain changes and hyperammonemia encephalopathy

There are very few domestic and international reports on this topic. Majority of articles associate hyperammonemia with the occurrence of encephalopathy, however not all cases of hyperammonemia lead to encephalopathy. Meanwhile, none of the studies indicated a correlation between the occurrence of hyperammonemic encephalopathy and ammonia levels. Some studies had suggested that when blood ammonia was generally elevated to 96.78 µmol/L, encephalopathy would be prone to occur, while the risk of coma increased dramatically (27). Since the body can self-regulate, elevated blood ammonia levels are reversible to some extent (23). Therefore, the occurrence of hyperammonemic encephalopathy in cancer patients may be closely related to the dose and formulation of 5-FU used, as well as the patient’s functional status, such as elderly patients, or patients with age-related brain changes, elderly dementia, and cachexia.

This patient was an elderly male with progressive wasting and age-related brain changes seen on head CT. He was orally taking Xeloda for 17 months. Long-term use of 5-FU can lead to neurotoxicity (16), which is mostly delayed and clinically rare, but unavoidable. Brain MRI can show similar age-related brain changes, such as subacute multifocal leukoencephalopathy, type II dementia, etc.

Hyperammonemia and age-related brain changes may be important factors contributing to the occurrence of hyperammonemic encephalopathy in this patient (28).

Induction factors

Some independent risk factors induced the occurrence of hyperammonemia and subsequent encephalopathy during chemotherapy (29). For example, some catabolic abnormalities were known to increase the risk of chemotherapy, including azotemia, liver dysfunction, humoral insufficiency, steroids, bacterial infections, gastrointestinal complications, and total parenteral nutrition (4,6). In this case, reduced tissue perfusion induced by a significant decrease in appetite and diarrhea which can further increase protein catabolism, nitrogen load and increased ammonium concentrations maybe the important induction factors for hyperammonemia encephalopathy.

Conclusions

The mechanism of 5-FU-induced hyperammonemic encephalopathy is unclear. The possible reasons for hyperammonemic encephalopathy were as follows: (I) due to the lack of DPD (the patient’s serum DPD level was 34.36 pg/mL by enzyme-linked immunosorbent assay (ELISA) with its reference value 960–3,060 pg/mL) (30), the continuous administration of 5-FU and limited metabolism caused rapid accumulation of 5-FU in the body, which entered the cerebrospinal fluid and caused acute myelinization of neurons, resulting in obvious gastrointestinal toxicity; (II) with the continuous infusion of 5-FU, the body’s DPD metabolic pathway may have negative feedback, and the metabolic products of 5-FU, such as fluoroacetic acid and fluorocitric acid, inhibit the tricarboxylic acid cycle, resulting in the accumulation of blood ammonia in the brain and ultimately leading to the occurrence of hyperammonemic encephalopathy; (III) according to the above theory, the loss of skeletal muscle in the patient led to a decrease in the number of mitochondria and damage to the tricarboxylic acid cycle, which may also explain the increase in ammonia due to the disturbance of the urea cycle.

Suggestion: (I) safety of 5-FU usage: early recognition and aggressive treatment may provide opportunities for more favorable outcomes before irreversible brain damage develops (31,32). (II) Dosage of 5-FU: the method of determining the dosage based on BSA is not the optimal choice. Changes in the patient’s weight did not affect the drug dose calculation based on BSA in all five cycles of chemotherapy. However, due to the altered tolerance, obvious adverse reactions occurred. In such special patient populations, therapeutic drug monitoring (TDM) which combined with the patient’s weight, infection status can be considered to monitor blood drug concentration and guide the 5-FU dosage. This calculation based on pharmacokinetics in clinical applications is being investigated in Europe and the United States, and significantly reduces adverse reactions (33). (III) Avoidance of induction: it is recommended to conduct a comprehensive evaluation of the patient’s physical condition before chemotherapy, including DPD testing, head MRI plain scan, liver and kidney function tests, weight, and other indicators, to avoid the use of 5-FU in cases of azotemia, liver dysfunction, humoral insufficiency, steroids, bacterial infections, gastrointestinal complications, and total parenteral nutrition. In the future, bioluminescence imaging (BLI) and CT, as non-invasive methods, are expected to evaluate whole-body microenvironment parameters. It will be helpful to evaluate patients’ tolerance to chemotherapy and guide treatment (34).

Acknowledgments

Funding: This research was funded by the Natural Science Foundation of Zhejiang Province (grant number LY20H290001).

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-23-167/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-23-167/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-23-167/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. WHO. Cancer. 2018. Available online: https://www.who.int/health-topics/cancer
2. Yeh KH, Cheng AL. High-dose 5-fluorouracil infusional therapy is associated with hyperammonaemia, lactic acidosis and encephalopathy. Br J Cancer 1997;75:464-5. [Crossref] [PubMed]
3. Okamura T, Kawachi Y, Nikkuni K, et al. A case of hyperammonemic encephalopathy related to 5-FU in an aged patient with recurrent colon cancer treated with FOLFIRI therapy. Gan To Kagaku Ryoho 2013;40:671-3. [PubMed]
4. Liaw CC, Wang HM, Wang CH, et al. Risk of transient hyperammonemic encephalopathy in cancer patients who received continuous infusion of 5-fluorouracil with the complication of dehydration and infection. Anticancer Drugs 1999;10:275-81. [Crossref] [PubMed]
5. Mitani S, Kadowaki S, Komori A, et al. Acute hyperammonemic encephalopathy after fluoropyrimidine-based chemotherapy: A case series and review of the literature. Medicine (Baltimore) 2017;96:e6874. [Crossref] [PubMed]
6. Mitchell RB, Wagner JE, Karp JE, et al. Syndrome of idiopathic hyperammonemia after high-dose chemotherapy: review of nine cases. Am J Med 1988;85:662-7. [Crossref] [PubMed]
7. Espinós J, Rifón J, Pérez-Calvo J, et al. Idiopathic hyperammonemia following high-dose chemotherapy. Bone Marrow Transplant 2006;37:899. [Crossref] [PubMed]
8. Martinelli G, Peccatori F, Ullrich B, et al. Clinical manifestation of severe hyperammonaemia in patients with multiple myeloma. Ann Oncol 1997;8:811. [Crossref] [PubMed]
9. Maestri NE, Clissold D, Brusilow SW. Neonatal onset ornithine transcarbamylase deficiency: A retrospective analysis. J Pediatr 1999;134:268-72. [Crossref] [PubMed]
10. Berry GT, Kaplan PB, Lichtenstein GR. Hyperammonia Possibly due to Corticosteroids. Arch Neurol 2000;57:1085-10856. [Crossref] [PubMed]
11. Karch FE, Lasagna L. Adverse drug reactions. A critical review. JAMA 1975;234:1236-41. [Crossref] [PubMed]
12. Li B, Gao R, Li R, et al. Discussion on the method of determining the correlation between adverse reactions/adverse events in clinical drug trials. Chinese Journal of New Drugs 2014;23:1465-70.
13. Kim YA, Chung HC, Choi HJ, et al. Intermediate dose 5-fluorouracil-induced encephalopathy. Jpn J Clin Oncol 2006;36:55-9. [Crossref] [PubMed]
14. Chen S, Hu X. Clinical characteristics and literature review of hyperammonemic encephalopathy associated with capecitabine. Central South Pharmacy 2018;16:1132-5.
15. Chen L, Wang R. A case of suspected fluorouracil-induced transient hyperammonemia. Chinese Journal of Hospital Pharmacy 2012;32:1594-5.
16. Franco DA, Greenberg HS. 5-FU multifocal inflammatory leukoencephalopathy and dihydropyrimidine dehydrogenase deficiency. Neurology 2001;56:110-2. [Crossref] [PubMed]
17. Israel ZH, Lossos A, Barak V, et al. Multifocal demyelinative leukoencephalopathy associated with 5-fluorouracil and levamisole. Acta Oncol 2000;39:117-20. [Crossref] [PubMed]
18. Martinez-Lapiscina EH, Erro ME, Cabada T, et al. 5-Fluorouracil induced hyperammonemic encephalophathy: etiopathologic correlation. Can J Neurol Sci 2012;39:553-4. [Crossref] [PubMed]
19. Yeh KH, Cheng AL. 5-Fluorouracil-related encephalopathy: at least two distinct pathogenetic mechanisms exist - reply. Br J Cancer 1998;77:1711-2. [Crossref]
20. Truman N, Nethercott D. Posterior reversible encephalopathy syndrome (PRES) after treatment with oxaliplatin and 5-fluorouracil. Clin Colorectal Cancer 2013;12:70-2. [Crossref] [PubMed]
21. Nishikawa Y, Funakoshi T, Horimatsu T, et al. Accumulation of alpha-fluoro-beta-alanine and fluoro mono acetate in a patient with 5-fluorouracil-associated hyperammonemia. Cancer Chemother Pharmacol 2017;79:629-33. [Crossref] [PubMed]
22. Thomas SA, Tomeh N, Theard S. Fluorouracil-induced Hyperammonemia in a Patient with Colorectal Cancer. Anticancer Res 2015;35:6761-3. [PubMed]
23. Lin YC, Chen JS, Wang CH, et al. Weekly high-dose 5-fluorouracil (5-FU), leucovorin (LV) and bimonthly cisplatin in patients with advanced gastric cancer. Jpn J Clin Oncol 2001;31:605-9. [Crossref] [PubMed]
24. Shi H, Su T. The effect of the tricarboxylic acid cycle and its influencing factors on exercise capacity. Liaoning Sports Science and Technology 2011;33:45-7+50.
25. Ji D. The effect of the tricarboxylic acid cycle on mitochondrial function under inflammatory and anti-inflammatory conditions. Shanghai Ocean University; 2020.
26. Lockwood AH, McDonald JM, Reiman RE, et al. The dynamics of ammonia metabolism in man. Effects of liver disease and hyperammonemia. J Clin Invest 1979;63:449-60. [Crossref] [PubMed]
27. Li Y, Liu X, Yao J, et al. Study on the relationship between blood ammonia level and cognitive impairment in patients with hepatitis B cirrhosis complicated with hepatic encephalopathy. Journal of Practical Hepatology 2022;25:74-8.
28. Li W. Progress in brain changes and imaging studies of normal brain aging and Alzheimer’s dementia. Chinese Journal of Medical Imaging Technology 1997;273-5.
29. Valik D. Encephalopathy, lactic acidosis, hyperammonaemia and 5-fluorouracil toxicity. Br J Cancer 1998;77:1710-2. [Crossref] [PubMed]
30. Zhou G, Zhou T, Zhou S, et al. The effect of depressive mood on dihydropyrimidine dehydrogenase levels in patients with malignant tumors. Today’s Pharmacy 2010;20:10-2+22.
31. Etienne MC, Lagrange JL, Dassonville O, et al. Population study of dihydropyrimidine dehydrogenase in cancer patients. J Clin Oncol 1994;12:2248-53. [Crossref] [PubMed]
32. Wu L, Wang H, Li J. Progress in pharmacogenetics of fluorouracil pharmacology and related metabolic enzymes. Zhejiang Clinical Medicine 2014;16:481-3.
33. He G, Xue H, Yang Q, et al. Establishment of a method for detecting blood concentration of fluorouracil and its clinical application. Chinese Pharmacist 2017;20:49-52.
34. Song WJ, Zhang F, Wang ZY, et al. Colorectal cancer mouse metastasis model combining bioluminescent and micro-computed tomography imaging for monitoring the effects of 5-fluorouracil treatment. Transl Cancer Res 2023;12:2572-81. [Crossref] [PubMed]