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A 5-Fluorouracil-Induced Hyperammonemic Encephalopathy Challenged with Capecitabine

A 5-Fluorouracil-Induced Hyperammonemic Encephalopathy Challenged with Capecitabine Hindawi Case Reports in Oncological Medicine Volume 2020, Article ID 4216752, 4 pages https://doi.org/10.1155/2020/4216752 Case Report A 5-Fluorouracil-Induced Hyperammonemic Encephalopathy Challenged with Capecitabine 1 1 2 2 Michael Chahin , Nithya Krishnan , Hardik Chhatrala, and Marwan Shaikh University of Florida College of Medicine–Jacksonville, Department of Medicine, Division of Internal Medicine, USA University of Florida College of Medicine–Jacksonville, Department of Medicine, Division of Hematology and Oncology, USA Correspondence should be addressed to Michael Chahin; michael.chahin@jax.ufl.edu Received 23 November 2019; Accepted 9 January 2020; Published 31 January 2020 Academic Editor: Jose I. Mayordomo Copyright © 2020 Michael Chahin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cancer patients presenting with altered mental status demand a broad differential with early recognition of the etiology. Failure to do so is associated with increased morbidity and mortality. Causes that must be considered include organ involvement of the cancer, electrolytes abnormalities, and even chemotherapeutic agents. A 32-year-old female patient had been recently started on FOLFOX for metastatic colon cancer. Her initial treatments were uneventful, but she later developed encephalopathy during day three of cycle five. During her evaluation, she was found to have hyperammonemia (84 mcmol/L), without hepatic failure, that resolved with stopping chemotherapy and supportive care. After a trial of home infusion fluorouracil, she developed hyperammonemic encephalopathy again. During both admissions, her symptoms resolved with IV hydration and cessation of chemotherapy. She was then successfully challenged with capecitabine (1000 mg/m daily), and additional hydration, and continued chemotherapy without recurrence of symptoms. Hyperammonemia is associated with fluorouracil though the mechanism is unclear. Suspected etiologies include either elevated levels of the drug due to slower metabolism or accumulation of certain metabolites. Additionally, risk factors such urease-producing bacterial infections, dehydration, and increased catabolism are thought to increase the risk for hyperammonemia. This case demonstrates the need for greater awareness of fluorouracil as a cause of hyperammonemic encephalopathy. Knowledge of this may allow for earlier recognition and reduced unnecessary testing. 1. Introduction 2. Case Presentation Confusion in the cancer patient can present a diagnostic A 32-year-old female with a history of iron deficiency anemia dilemma. It is often multifactorial, possibly due to the delir- presented with bright red blood per rectum and worsening ium from the malignancy itself, electrolyte abnormalities, anemia that lead to the diagnosis of an invasive rectosigmoid organ involvement, and even the cancer treatment. Certain colonic adenocarcinoma. The tumor was microsatellite chemotherapy drugs, such as cytarabine and methotrexate, stable, KRAs mutated, and BRAF wild type. A positron emis- are associated with delirium. Early diagnosis is crucial as sion tomography scan revealed increased uptake in the recto- delirium in the cancer patient conveys increased morbidity sigmoid lesion, retroperitoneal lymph nodes, and numerous and mortality [1]. Factors that increase the risk for the liver lesions. Brain magnetic resonance imaging did not show development of delirium include age > 70 years, cognitive brain metastasis. Her Eastern Cooperative Oncology Group impairment, and end-stage organ dysfunction [2]. One (ECOG) Performance Status was zero. must keep in mind that these patients often develop She was started on FOLFOX and bevacizumab chemo- hypoactive delirium, which could delay diagnosis if not therapy. Her regimen was folinic acid 400 mg/m once on recognized [1, 3]. We present a patient who developed day one, 5-FU 400 mg/m bolus on day one followed by hyperammonemic encephalopathy following treatment with 2400 mg/m continuous infusion over 46 hours, oxaliplatin 5-fluorouracil (5-FU) for metastatic colon cancer. 85 mg/m once on day one, and bevacizumab 5 mg/kg once 2 Case Reports in Oncological Medicine Table 1 Reference range Two days before admission Day of admission Sodium 135-145 mmol/L 142 144 Potassium 3.3-4.6 mmol/L 4.0 4.9 Chloride 101-110 mmol/L 106 108 Carbon dioxide 21-29 mmol/L 25 13 Urea nitrogen 6-22 mg/dL 9 17 Creatinine 0.51-0.95 mg/dL 0.65 0.96 Glucose 71-99 mg/dL 96 73 Calcium 8.6-10.0 mg/dL 9.4 9.4 Anion gap 4-16 mmol/L 11 23 Total protein 6.5-8.3 g/dL 7.3 7.7 Albumin 3.8-4.9 g/dL 4.3 4.6 AST 14-33 IU/L 17 40 ALT 10-42 IU/L 14 48 Direct bilirubin 0.0-0.2 mg/dL 0.3 Indirect bilirubin <0.8 mg/dL 1.4 Total bilirubin 0.2-1.0 mg/dL 0.4 1.7 Alkaline phosphatase 35-104 IU/L 66 82 Ammonia 11-35 mcmol/L 84 Lactic acid 0.7-2.7 mmol/L 10.4 on day one. She tolerated cycles 1-4 with mild nausea and switched to capecitabine 1000 mg/m and oxaliplatin vomiting. During the third day of cycle five, she became (CAPEOX) and bevacizumab. Her weight had remained acutely altered and developed nausea and vomiting beyond stable since starting chemotherapy, but she had appeared what she had with the initial two days of chemotherapy. dehydrated during clinic visits. She was encouraged to take The 46-hour infusion of 5-FU has been completed the night in more fluids and was given IV fluids during chemotherapy before, and she had presented to the infusion center that sessions. She was advised to cease using lactulose since there morning for pump removal. An emergency department was no overt hepatic failure. She had no recurrence of evaluation was advised due marked lethargy. She was hyperammonemia symptoms while on CAPEOX, for a total oriented to person and place but not to time or situation. of eight cycles. A dihydropyrimidine dehydrogenase (DPD) Her gait was ataxic, she a mild tremor, and her speech was level had been ordered during the previous admission and minimally comprehensible. Her Glasgow Coma Score was normal. Based on these findings, her hyperammonemia (GCS) was 12. Her spouse endorsed that she felt weak and was attributed to 5-FU. had some vomiting the night before. No recent constipation. CT head was unremarkable (Table 1). 3. Discussion She was given intravenous fluids, observed overnight, and discharged home after symptom resolution. Her lactic acido- Colon cancer is the third most common cause of cancer- sis and acute kidney injury resolved. Empiric broad spectrum related death in the United States [4]. The mainstays of che- antibiotics had been given but were stopped due to negative motherapy are folinic acid, 5-fluorouracil, and oxaliplatin infectious workup and rapid improvement with hydration. (FOLFOX), and folinic acid, 5-FU, and irinotecan (FOLFIRI) She received lactulose and her chemotherapy was held while [5]. Capecitabine and oxaliplatin (CAPOX) can be used as an inpatient. She did not recall much from her presentation. oral alternative to FOLFOX [5, 6]. This patient tolerated cap- For cycle six of chemotherapy she was started on 5-FU ecitabine, without recurrence of her hyperammonemia. alone for a home infusion over 46 hours, folinic acid, and The mechanism of fluorouracil-induced hyperammone- bevacizumab therapy. On day one of treatment, shortly after mic encephalopathy is unclear but likely multifactorial. Defi- starting the 5-FU infusion, she again developed altered ciency in DPD, the primary enzyme in the metabolism of 5- mental status. Her physical exam was significant for asterixis, FU, may play a role though this patient’s DPD activity was nonverbal status, and not following commands. She was not normal [7]. Another possible etiology is inhibition of the ambulating. Her GCS was eight this time. She was treated Krebs cycle by fluoroacetate or fluorocitrate, metabolites of with fluids until symptom resolution and was discharged. 5-FU, leading to excess urea and the subsequent accumula- Lactulose had been resumed while inpatient, and she was to tion of ammonia [7, 8]. continue it at discharge (Table 2). It has been proposed as well that 5-FU therapy alone Having developed hyperammonemic encephalopathy in does not generally induce hyperammonemia. Rather, the previous two chemotherapy regimens, she was then weight loss, dehydration, constipation, bacterial infection, Case Reports in Oncological Medicine 3 kidney injury in this patient was a result of dehydration but Table 2 could still have been a risk factor for hyperammonemia. Day of Reference range second admission 4. Conclusion Sodium 135-145 mmol/L 139 Given the prevalence of colon cancer, the primary care, Potassium 3.3-4.6 mmol/L 4.5 hospitalist, and emergency physician should be wary of Chloride 101-110 mmol/L 101 5-FU causing hyperammonemia. This patient was treated Carbon dioxide 21-29 mmol/L 15 with lactulose despite not having hepatic damage. Though Urea nitrogen 6-22 mg/dL 18 one should have a broad differential, in a cancer patient, Creatinine 0.51-0.95 mg/dL 1.13 presenting with confusion recognition of this adverse effect Glucose 71-99 mg/dL 94 of 5-FU may reduce unnecessary testing. Additionally, this Calcium 8.6-10.0 mg/dL 10.6 case demonstrates that patients with 5-FU-induced hyper- ammonemic encephalopathy may be challenged with Anion gap 4-16 mmol/L 23 capecitabine though the risk of encephalopathy remains. Total protein 6.5-8.3 g/dL 9.0 Treatment should be focused on reducing risk factors for Albumin 3.8-4.9 g/dL 5.1 hyperammonemia. AST 14-33 IU/L 24 ALT 10-42 IU/L 27 Conflicts of Interest Direct bilirubin 0.0-0.2 mg/dL 0.3 The authors declare that they have no conflicts of interest. Indirect bilirubin <0.8 mg/dL 1.1 Total bilirubin 0.2-1.0 mg/dL 1.4 References Alkaline phosphatase 35-104 IU/L 89 Ammonia 11-35 mcmol/L 290 [1] C. Nolan and L. M. Deangelis, “The confused oncologic Lactic acid 0.7-2.7 mmol/L 8.2 patient: a rational clinical approach,” Current Opinion in Neurology, vol. 29, no. 6, pp. 789–796, 2016. [2] S. H. Bush, P. G. Lawlor, K. Ryan et al., “Delirium in adult and renal impairment are predisposing factors. Chronic con- cancer patients: ESMO Clinical Practice Guidelines,” Annals stipation leading to increased bacterial urease and amino acid of Oncology, vol. 29, Supplement 4, pp. iv143–iv165, 2018. oxidase activity and increased catabolism in chronically [3] M. De la Cruz, J. Fan, S. Yennu et al., “The frequency of missed anorexic patients also contribute to a hyperammonemic state delirium in patients referred to palliative care in a comprehen- [9]. Urinary tract infection due to urease-producing bacteria sive cancer center,” Supportive Care in Cancer, vol. 23, no. 8, is associated with hyperammonemia, independently of 5-FU pp. 2427–2433, 2015. [10]. Renal impairment is thought to increase levels of 5-FU [4] A. R. Marley and H. Nan, “Epidemiology of colorectal cancer,” and 5-fluoro-beta-alanine (FBAL), another metabolite of International Journal of Molecular Epidemiology and Genetics, 5-FU [9, 11]. Direct neurotoxicity from these agents is vol. 7, no. 3, pp. 105–114, 2016. possible based on a study conducted in cats that revealed, [5] National Comprehensive Cancer Network, “Colon cancer similar, neuropathologic changes in subjects with intraven- (Version 2.2019),” September 2019, https://www.nccn.org/ professionals/physician_gls/pdf/colon.pdf. tricular administration of FBAL and 5-FU given orally [12]. [6] C. Aguado, B. Garcia-Paredes, M. J. Sotelo, J. Sastre, and Hyperammonemia, in general, is most commonly due to E. Diaz-Rubio, “Should capecitabine replace 5-fluorouracil in liver damage but there are many other causes that must be the first-line treatment of metastatic colorectal cancer?,” considered. Some causes, in addition to urinary tract infec- World Journal of Gastroenterology, vol. 20, no. 20, pp. 6092– tion, are due to urease-producing bacteria, excessive amino 6101, 2014. acid load from gastrointestinal hemorrhage, anticonvulsants, [7] Y. A. Kim, H. C. Chung, H. J. Choi, S. Y. Rha, J. S. Seong, and such as topiramate, and urea cycle defects [10]. Multiple che- H. C. Jeung, “Intermediate dose 5-fluorouracil-induced motherapy agents, in addition to 5-FU, have been implicated encephalopathy,” Japanese Journal of Clinical Oncology, in hyperammonemic encephalopathy [13]. Though these vol. 36, no. 1, pp. 55–59, 2006. have not been specifically associated with fluorouracil- [8] S. A. Thomas, N. Tomeh, and S. Theard, “Fluorouracil- induced hyperammonemic encephalopathy, they likely pre- induced hyperammonemia in a patient with colorectal can- dispose patients to developing it. A case series demonstrated cer,” Anticancer Research, vol. 35, no. 12, pp. 6761–6763, 2015. hyperammonemic encephalopathy in 5-FU and oral fluoro- [9] S. Kikuta, T. Asakage, K. Nakao, M. Sugasawa, and A. Kubota, pyrimidine agents. Most of the patients had risk factors in “The aggravating factors of hyperammonemia related to 5- common such as dehydration and sarcopenia [14]. fluorouracil infusion—a report of two cases,” Auris, Nasus, A rechallenge protocol has been suggested in the context Larynx, vol. 35, no. 2, pp. 295–299, 2008. of hyperammonemic encephalopathy after receiving 5-FU, [10] V. Walker, “Severe hyperammonaemia in adults not explained oxaliplatin, irinocetan, and folinic acid (FOLFIRINOX) by liver disease,” Annals of Clinical Biochemistry, vol. 49, [15]. The management of the patient presented above was Part 3, pp. 214–228, 2012. focused on mitigating her primary risk factor for hyperam- [11] C. C. Liaw, H. M. Wang, C. H. Wang et al., “Risk of transient monemia, which was dehydration. It is likely that the acute hyperammonemic encephalopathy in cancer patients who 4 Case Reports in Oncological Medicine received continuous infusion of 5-fluorouracil with the complication of dehydration and infection,” Anti-Cancer Drugs, vol. 10, no. 3, pp. 275–281, 1999. [12] R. Okeda, M. Shibutani, T. Matsuo, T. Kuroiwa, R. Shimokawa, and T. Tajima, “Experimental neurotoxicity of 5-fluorouracil and its derivatives is due to poisoning by the monofluorinated organic metabolites, monofluoroacetic acid and alpha-fluoro-beta-alanine,” Acta Neuropathologica, vol. 81, no. 1, pp. 66–73, 1990. [13] K. J. Willson, L. M. Nott, V. T. Broadbridge, and T. Price, “Hepatic encephalopathy associated with cancer or anticancer therapy,” Gastrointestinal Cancer Research, vol. 6, no. 1, pp. 11–16, 2013. [14] S. Mitani, S. Kadowaki, A. Komori et al., “Acute hyperammo- nemic encephalopathy after fluoropyrimidine-based chemo- therapy,” Medicine, vol. 96, no. 22, article e6874, 2017. [15] A. Boilève, C. Wicker, B. Verrt et al., “5-fluorouracil rechal- lenge after 5-fluorouracil-induced hyperammonemic encepha- lopathy,” Anti-Cancer Drugs, vol. 30, no. 3, pp. 313–317, 2019. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Oncological Medicine Hindawi Publishing Corporation

A 5-Fluorouracil-Induced Hyperammonemic Encephalopathy Challenged with Capecitabine

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Copyright © 2020 Michael Chahin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

Hindawi Case Reports in Oncological Medicine Volume 2020, Article ID 4216752, 4 pages https://doi.org/10.1155/2020/4216752 Case Report A 5-Fluorouracil-Induced Hyperammonemic Encephalopathy Challenged with Capecitabine 1 1 2 2 Michael Chahin , Nithya Krishnan , Hardik Chhatrala, and Marwan Shaikh University of Florida College of Medicine–Jacksonville, Department of Medicine, Division of Internal Medicine, USA University of Florida College of Medicine–Jacksonville, Department of Medicine, Division of Hematology and Oncology, USA Correspondence should be addressed to Michael Chahin; michael.chahin@jax.ufl.edu Received 23 November 2019; Accepted 9 January 2020; Published 31 January 2020 Academic Editor: Jose I. Mayordomo Copyright © 2020 Michael Chahin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cancer patients presenting with altered mental status demand a broad differential with early recognition of the etiology. Failure to do so is associated with increased morbidity and mortality. Causes that must be considered include organ involvement of the cancer, electrolytes abnormalities, and even chemotherapeutic agents. A 32-year-old female patient had been recently started on FOLFOX for metastatic colon cancer. Her initial treatments were uneventful, but she later developed encephalopathy during day three of cycle five. During her evaluation, she was found to have hyperammonemia (84 mcmol/L), without hepatic failure, that resolved with stopping chemotherapy and supportive care. After a trial of home infusion fluorouracil, she developed hyperammonemic encephalopathy again. During both admissions, her symptoms resolved with IV hydration and cessation of chemotherapy. She was then successfully challenged with capecitabine (1000 mg/m daily), and additional hydration, and continued chemotherapy without recurrence of symptoms. Hyperammonemia is associated with fluorouracil though the mechanism is unclear. Suspected etiologies include either elevated levels of the drug due to slower metabolism or accumulation of certain metabolites. Additionally, risk factors such urease-producing bacterial infections, dehydration, and increased catabolism are thought to increase the risk for hyperammonemia. This case demonstrates the need for greater awareness of fluorouracil as a cause of hyperammonemic encephalopathy. Knowledge of this may allow for earlier recognition and reduced unnecessary testing. 1. Introduction 2. Case Presentation Confusion in the cancer patient can present a diagnostic A 32-year-old female with a history of iron deficiency anemia dilemma. It is often multifactorial, possibly due to the delir- presented with bright red blood per rectum and worsening ium from the malignancy itself, electrolyte abnormalities, anemia that lead to the diagnosis of an invasive rectosigmoid organ involvement, and even the cancer treatment. Certain colonic adenocarcinoma. The tumor was microsatellite chemotherapy drugs, such as cytarabine and methotrexate, stable, KRAs mutated, and BRAF wild type. A positron emis- are associated with delirium. Early diagnosis is crucial as sion tomography scan revealed increased uptake in the recto- delirium in the cancer patient conveys increased morbidity sigmoid lesion, retroperitoneal lymph nodes, and numerous and mortality [1]. Factors that increase the risk for the liver lesions. Brain magnetic resonance imaging did not show development of delirium include age > 70 years, cognitive brain metastasis. Her Eastern Cooperative Oncology Group impairment, and end-stage organ dysfunction [2]. One (ECOG) Performance Status was zero. must keep in mind that these patients often develop She was started on FOLFOX and bevacizumab chemo- hypoactive delirium, which could delay diagnosis if not therapy. Her regimen was folinic acid 400 mg/m once on recognized [1, 3]. We present a patient who developed day one, 5-FU 400 mg/m bolus on day one followed by hyperammonemic encephalopathy following treatment with 2400 mg/m continuous infusion over 46 hours, oxaliplatin 5-fluorouracil (5-FU) for metastatic colon cancer. 85 mg/m once on day one, and bevacizumab 5 mg/kg once 2 Case Reports in Oncological Medicine Table 1 Reference range Two days before admission Day of admission Sodium 135-145 mmol/L 142 144 Potassium 3.3-4.6 mmol/L 4.0 4.9 Chloride 101-110 mmol/L 106 108 Carbon dioxide 21-29 mmol/L 25 13 Urea nitrogen 6-22 mg/dL 9 17 Creatinine 0.51-0.95 mg/dL 0.65 0.96 Glucose 71-99 mg/dL 96 73 Calcium 8.6-10.0 mg/dL 9.4 9.4 Anion gap 4-16 mmol/L 11 23 Total protein 6.5-8.3 g/dL 7.3 7.7 Albumin 3.8-4.9 g/dL 4.3 4.6 AST 14-33 IU/L 17 40 ALT 10-42 IU/L 14 48 Direct bilirubin 0.0-0.2 mg/dL 0.3 Indirect bilirubin <0.8 mg/dL 1.4 Total bilirubin 0.2-1.0 mg/dL 0.4 1.7 Alkaline phosphatase 35-104 IU/L 66 82 Ammonia 11-35 mcmol/L 84 Lactic acid 0.7-2.7 mmol/L 10.4 on day one. She tolerated cycles 1-4 with mild nausea and switched to capecitabine 1000 mg/m and oxaliplatin vomiting. During the third day of cycle five, she became (CAPEOX) and bevacizumab. Her weight had remained acutely altered and developed nausea and vomiting beyond stable since starting chemotherapy, but she had appeared what she had with the initial two days of chemotherapy. dehydrated during clinic visits. She was encouraged to take The 46-hour infusion of 5-FU has been completed the night in more fluids and was given IV fluids during chemotherapy before, and she had presented to the infusion center that sessions. She was advised to cease using lactulose since there morning for pump removal. An emergency department was no overt hepatic failure. She had no recurrence of evaluation was advised due marked lethargy. She was hyperammonemia symptoms while on CAPEOX, for a total oriented to person and place but not to time or situation. of eight cycles. A dihydropyrimidine dehydrogenase (DPD) Her gait was ataxic, she a mild tremor, and her speech was level had been ordered during the previous admission and minimally comprehensible. Her Glasgow Coma Score was normal. Based on these findings, her hyperammonemia (GCS) was 12. Her spouse endorsed that she felt weak and was attributed to 5-FU. had some vomiting the night before. No recent constipation. CT head was unremarkable (Table 1). 3. Discussion She was given intravenous fluids, observed overnight, and discharged home after symptom resolution. Her lactic acido- Colon cancer is the third most common cause of cancer- sis and acute kidney injury resolved. Empiric broad spectrum related death in the United States [4]. The mainstays of che- antibiotics had been given but were stopped due to negative motherapy are folinic acid, 5-fluorouracil, and oxaliplatin infectious workup and rapid improvement with hydration. (FOLFOX), and folinic acid, 5-FU, and irinotecan (FOLFIRI) She received lactulose and her chemotherapy was held while [5]. Capecitabine and oxaliplatin (CAPOX) can be used as an inpatient. She did not recall much from her presentation. oral alternative to FOLFOX [5, 6]. This patient tolerated cap- For cycle six of chemotherapy she was started on 5-FU ecitabine, without recurrence of her hyperammonemia. alone for a home infusion over 46 hours, folinic acid, and The mechanism of fluorouracil-induced hyperammone- bevacizumab therapy. On day one of treatment, shortly after mic encephalopathy is unclear but likely multifactorial. Defi- starting the 5-FU infusion, she again developed altered ciency in DPD, the primary enzyme in the metabolism of 5- mental status. Her physical exam was significant for asterixis, FU, may play a role though this patient’s DPD activity was nonverbal status, and not following commands. She was not normal [7]. Another possible etiology is inhibition of the ambulating. Her GCS was eight this time. She was treated Krebs cycle by fluoroacetate or fluorocitrate, metabolites of with fluids until symptom resolution and was discharged. 5-FU, leading to excess urea and the subsequent accumula- Lactulose had been resumed while inpatient, and she was to tion of ammonia [7, 8]. continue it at discharge (Table 2). It has been proposed as well that 5-FU therapy alone Having developed hyperammonemic encephalopathy in does not generally induce hyperammonemia. Rather, the previous two chemotherapy regimens, she was then weight loss, dehydration, constipation, bacterial infection, Case Reports in Oncological Medicine 3 kidney injury in this patient was a result of dehydration but Table 2 could still have been a risk factor for hyperammonemia. Day of Reference range second admission 4. Conclusion Sodium 135-145 mmol/L 139 Given the prevalence of colon cancer, the primary care, Potassium 3.3-4.6 mmol/L 4.5 hospitalist, and emergency physician should be wary of Chloride 101-110 mmol/L 101 5-FU causing hyperammonemia. This patient was treated Carbon dioxide 21-29 mmol/L 15 with lactulose despite not having hepatic damage. Though Urea nitrogen 6-22 mg/dL 18 one should have a broad differential, in a cancer patient, Creatinine 0.51-0.95 mg/dL 1.13 presenting with confusion recognition of this adverse effect Glucose 71-99 mg/dL 94 of 5-FU may reduce unnecessary testing. Additionally, this Calcium 8.6-10.0 mg/dL 10.6 case demonstrates that patients with 5-FU-induced hyper- ammonemic encephalopathy may be challenged with Anion gap 4-16 mmol/L 23 capecitabine though the risk of encephalopathy remains. Total protein 6.5-8.3 g/dL 9.0 Treatment should be focused on reducing risk factors for Albumin 3.8-4.9 g/dL 5.1 hyperammonemia. AST 14-33 IU/L 24 ALT 10-42 IU/L 27 Conflicts of Interest Direct bilirubin 0.0-0.2 mg/dL 0.3 The authors declare that they have no conflicts of interest. Indirect bilirubin <0.8 mg/dL 1.1 Total bilirubin 0.2-1.0 mg/dL 1.4 References Alkaline phosphatase 35-104 IU/L 89 Ammonia 11-35 mcmol/L 290 [1] C. Nolan and L. M. Deangelis, “The confused oncologic Lactic acid 0.7-2.7 mmol/L 8.2 patient: a rational clinical approach,” Current Opinion in Neurology, vol. 29, no. 6, pp. 789–796, 2016. [2] S. H. Bush, P. G. Lawlor, K. Ryan et al., “Delirium in adult and renal impairment are predisposing factors. Chronic con- cancer patients: ESMO Clinical Practice Guidelines,” Annals stipation leading to increased bacterial urease and amino acid of Oncology, vol. 29, Supplement 4, pp. iv143–iv165, 2018. oxidase activity and increased catabolism in chronically [3] M. De la Cruz, J. Fan, S. Yennu et al., “The frequency of missed anorexic patients also contribute to a hyperammonemic state delirium in patients referred to palliative care in a comprehen- [9]. Urinary tract infection due to urease-producing bacteria sive cancer center,” Supportive Care in Cancer, vol. 23, no. 8, is associated with hyperammonemia, independently of 5-FU pp. 2427–2433, 2015. [10]. Renal impairment is thought to increase levels of 5-FU [4] A. R. Marley and H. Nan, “Epidemiology of colorectal cancer,” and 5-fluoro-beta-alanine (FBAL), another metabolite of International Journal of Molecular Epidemiology and Genetics, 5-FU [9, 11]. Direct neurotoxicity from these agents is vol. 7, no. 3, pp. 105–114, 2016. possible based on a study conducted in cats that revealed, [5] National Comprehensive Cancer Network, “Colon cancer similar, neuropathologic changes in subjects with intraven- (Version 2.2019),” September 2019, https://www.nccn.org/ professionals/physician_gls/pdf/colon.pdf. tricular administration of FBAL and 5-FU given orally [12]. [6] C. Aguado, B. Garcia-Paredes, M. J. Sotelo, J. Sastre, and Hyperammonemia, in general, is most commonly due to E. Diaz-Rubio, “Should capecitabine replace 5-fluorouracil in liver damage but there are many other causes that must be the first-line treatment of metastatic colorectal cancer?,” considered. Some causes, in addition to urinary tract infec- World Journal of Gastroenterology, vol. 20, no. 20, pp. 6092– tion, are due to urease-producing bacteria, excessive amino 6101, 2014. acid load from gastrointestinal hemorrhage, anticonvulsants, [7] Y. A. Kim, H. C. Chung, H. J. Choi, S. Y. Rha, J. S. Seong, and such as topiramate, and urea cycle defects [10]. Multiple che- H. C. Jeung, “Intermediate dose 5-fluorouracil-induced motherapy agents, in addition to 5-FU, have been implicated encephalopathy,” Japanese Journal of Clinical Oncology, in hyperammonemic encephalopathy [13]. Though these vol. 36, no. 1, pp. 55–59, 2006. have not been specifically associated with fluorouracil- [8] S. A. Thomas, N. Tomeh, and S. Theard, “Fluorouracil- induced hyperammonemic encephalopathy, they likely pre- induced hyperammonemia in a patient with colorectal can- dispose patients to developing it. A case series demonstrated cer,” Anticancer Research, vol. 35, no. 12, pp. 6761–6763, 2015. hyperammonemic encephalopathy in 5-FU and oral fluoro- [9] S. Kikuta, T. Asakage, K. Nakao, M. Sugasawa, and A. Kubota, pyrimidine agents. Most of the patients had risk factors in “The aggravating factors of hyperammonemia related to 5- common such as dehydration and sarcopenia [14]. fluorouracil infusion—a report of two cases,” Auris, Nasus, A rechallenge protocol has been suggested in the context Larynx, vol. 35, no. 2, pp. 295–299, 2008. of hyperammonemic encephalopathy after receiving 5-FU, [10] V. Walker, “Severe hyperammonaemia in adults not explained oxaliplatin, irinocetan, and folinic acid (FOLFIRINOX) by liver disease,” Annals of Clinical Biochemistry, vol. 49, [15]. The management of the patient presented above was Part 3, pp. 214–228, 2012. focused on mitigating her primary risk factor for hyperam- [11] C. C. Liaw, H. M. Wang, C. H. Wang et al., “Risk of transient monemia, which was dehydration. It is likely that the acute hyperammonemic encephalopathy in cancer patients who 4 Case Reports in Oncological Medicine received continuous infusion of 5-fluorouracil with the complication of dehydration and infection,” Anti-Cancer Drugs, vol. 10, no. 3, pp. 275–281, 1999. [12] R. Okeda, M. Shibutani, T. Matsuo, T. Kuroiwa, R. Shimokawa, and T. Tajima, “Experimental neurotoxicity of 5-fluorouracil and its derivatives is due to poisoning by the monofluorinated organic metabolites, monofluoroacetic acid and alpha-fluoro-beta-alanine,” Acta Neuropathologica, vol. 81, no. 1, pp. 66–73, 1990. [13] K. J. Willson, L. M. Nott, V. T. Broadbridge, and T. Price, “Hepatic encephalopathy associated with cancer or anticancer therapy,” Gastrointestinal Cancer Research, vol. 6, no. 1, pp. 11–16, 2013. [14] S. Mitani, S. Kadowaki, A. Komori et al., “Acute hyperammo- nemic encephalopathy after fluoropyrimidine-based chemo- therapy,” Medicine, vol. 96, no. 22, article e6874, 2017. [15] A. Boilève, C. Wicker, B. Verrt et al., “5-fluorouracil rechal- lenge after 5-fluorouracil-induced hyperammonemic encepha- lopathy,” Anti-Cancer Drugs, vol. 30, no. 3, pp. 313–317, 2019.

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Published: Jan 31, 2020

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