A Case of Hyperammonemia Associated with High Dihydropyrimidine Dehydrogenase Activity

Hindawi Publishing Corporation Case Reports in Oncological Medicine Volume 2016, Article ID 7510901, 4 pages http://dx.doi.org/10.1155/2016/7510901 Case Report A Case of Hyperammonemia Associated with High Dihydropyrimidine Dehydrogenase Activity Keiki Nagaharu,1 Kenji Ikemura,2 Yoshiki Yamashita,3 Hiroyasu Oda,3 Mikiya Ishihara,3 Yumiko Sugawara,3 Satoshi Tamaru,3 Toshiro Mizuno,3 and Naoyuki Katayama3 1 Department of Hematology and Oncology, Suzuka General Hospital, Yamanohana, Yasuzuka, Suzuka, Mie Prefecture 1275-53, Japan Department of Pharmacy, Mie University Hospital, Edobashi 2-174, Tsu, Mie Prefecture 514-8507, Japan 3 Department of Hematology and Oncology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie Prefecture 514-8507, Japan 2 Correspondence should be addressed to Keiki Nagaharu; Received 9 October 2015; Accepted 20 December 2015 Academic Editor: Raffaele Palmirotta Copyright © 2016 Keiki Nagaharu 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. Over the past decades, 5-Fluorouracil (5-FU) has been widely used to treat several types of carcinoma, including esophageal squamous cell carcinoma. In addition to its common side effects, including diarrhea, mucositis, neutropenia, and anemia, 5FU treatment has also been reported to cause hyperammonemia. However, the exact mechanism responsible for 5-FU-induced hyperammonemia remains unknown. We encountered an esophageal carcinoma patient who developed hyperammonemia when receiving 5-FU-containing chemotherapy but did not exhibit any of the other common adverse effects of 5-FU treatment. At the onset of hyperammonemia, laboratory tests revealed high dihydropyrimidine dehydrogenase (DPD) activity and rapid 5-FU clearance. Our findings suggested that 5-FU hypermetabolism may be one of the key mechanisms responsible for hyperammonemia during 5-FU treatment. 1. Introduction 2. Case Report In 1957, Heidelberger et al. reported the use of 5-FU as a new antitumoral drug [1], and at present, 5-FU is one of the most commonly used anticancer drugs around the world. A combination of cisplatin and 5-FU is often used for first-line chemotherapy in unresectable cases of advanced esophageal carcinoma. As is the case for other anticancer drugs, the most common side effects of 5-FU, such as diarrhea, mucositis, neutropenia, and anemia, are due to its effects on the bone marrow and gastrointestinal epithelium. These common adverse effects are observed in more than half of the patients treated with 5-FU-containing regimens [2]. On the other hand, the prevalence of 5-FU-induced hyperammonemia has been reported to range within 5.7%– 7.0% [3–5]. The exact mechanism responsible for 5-FUinduced hyperammonemia remains unknown. Herein, we report a patient who developed recurrent hyperammonemia. A 60-year-old man presented with a 1-month history of progressively worsening discomfort during swallowing. His medical history included treated gastric cancer (5 years earlier) and emphysema. The patient reported that he had smoked approximately 20 cigarettes per day since the age of 20. Laboratory tests did not detect hepatic disorders or renal problems. Upper gastrointestinal endoscopy revealed an ulcerative lesion with elevated distinct borders in the lower esophagus, and endoscopic ultrasound detected serosal invasion. The lesion was diagnosed as a squamous cell carcinoma from a biopsy. A positron emission tomography (PET) examination confirmed lung metastasis. As a result, the patient was clinically staged as cT3N1M1 and was treated with 5-FU and cisplatin. However, his obstructive swallowing problems continued to worsen. We next administered concurrent radiotherapy as a palliative treatment. The treatment regimen (FP regimen) consisted of 5-FU at a dose of 2 Case Reports in Oncological Medicine Table 1: Laboratory findings. [Peripheral blood] WBC RBC Hb Ht MCV Plt [Coagulation test] APTT PT D-dimer [Biochemistry] TP Alb AST ALT LDH 𝛾-GTP T-Bil Glu BUN Cre Na K Cl CRP NH3 5-FU concentration Day of onset The following day [Normal range] 8080/𝜇L 382 × 104 /𝜇L 15.3 g/dL 33.3% 87.2 fL 26.3 × 104 /𝜇L 5180/𝜇L 414 × 104 /𝜇L 12.9 g/dL 37.0% 89.4 fL 25.6 × 104 /𝜇L 3500–9000/𝜇L 376–500 × 104 /𝜇L 11.3–15.2 g/dL 33.4–44.9% 82.7–101 fL 13.0–36.9 × 104 /𝜇L 31.0 sec 14.2 sec 0.66 𝜇g/mL 6.2 g/dL 3.4 g/dL 20 IU/L 25 IU/L 182 IU/L 0.6 mg/dL 101 mg/dL 34 mg/dL 0.95 mg/dL 129 mEq/L 2.6 mEq/L 93 mEq/L 0.47 mg/dL 131 𝜇g/dL 13 ng/mL 25.0–45.0 sec 13.5–15.0 sec <0.50 𝜇g/mL 5.6 g/dL 3.4 g/dL 20 IU/L 23 IU/L 155 IU/L 50 IU/L 0.60 mg/dL 6.5–8.5 g/dL 4.1–5.3 g/dL 10–35 IU/L 10–35 IU/L 110–225 IU/L 8–60 IU/L 0.2–1.3 mg/dL 80–120 mg/dL 9.6–22.0 mg/dL <1.20 mg/dL 138–145 mEq/L 3.4–4.7 mEq/L 99–108 mEq/L <0.30 mg/dL <18 𝜇g/dL 600 ng/mL (steady state) 31 mg/dL 1.09 mg/dL 136 mEq/L 3.1 mEq/L 97 mEq/L 0.44 mg/dL 44 𝜇g/dL <10 ng/mL Laboratory findings revealed hyperammonemia and mild hyponatremia. Serum concentration of 5-FU was low. 800 mg/m2 on days 1–5 and cisplatin at a dose of 80 mg/m2 on day 1 and was repeated every 28 days. The patient did not exhibit specific adverse effects during the first course of treatment. After the completion of that, a second course of the same regimen was started. However, the patient fell unconscious 72 hours after the initiation of treatment. On physical examination, he was unconscious (Glasgow Coma Scale: E1V3M5) and afebrile and had a pulse rate of 69 bpm and a blood pressure of 111/61 mmHg. There were no signs of mucositis. A neurological examination did not detect paralysis or abnormal reflexes. The patient’s laboratory data revealed hyperammonemia, mild hyponatremia, and a high blood urea nitrogen (BUN) level. Other findings are shown in Table 1. Radiological assessments including computed tomography (CT) and magnetic resonance imaging (MRI) scans of the patient’s head did not detect any apparent cause of the patient’s condition. On the following day, his condition normalized with only normal saline hydration, and he did not exhibit sequelae. We subsequently diagnosed the patient with 5-FU-related hyperammonemia. Table 2: Urinary analysis of dihydrouracil and uracil. Patient’s value Normal range [6] Dihydrouracil 5.325 𝜇g/mL 1.7–13.1 𝜇g/mL Uracil 0.495 𝜇g/mL 4–30 𝜇g/mL Ratio 10.75 0.3–0.77 Urinary DHU/U was much higher than normal. These findings supported the high activity of dihydropyrimidine dehydrogenase. At the onset of hyperammonemia, the patient’s serum 5-FU concentration during the unconscious state was significantly lower (13 ng/mL) than the normal range (500– 600 ng/mL). In 5-FU metabolism, approximately 80% of infused 5-FU is degraded by DPD, the initial and ratelimiting enzyme in the catabolism of pyrimidine bases, and this process produces ammonia as the end product. Due to the rapid clearance of 5-FU, (...truncated)