- Email: [email protected]
Unusual causes of hyperammonemia in the ED
Diagnostics
Unusual Causes of Hyperammonemia in the ED TE-I WENG, MD, FRANK FUH-YUAN SHIH, MD, AND WEN-JONE CHEN, MD, PHD Plasma ammonia measurement is a simple yet important screening in the ED for patients with unexplained stupor or delirium. Acute hyperammonemia is a medical emergency for which immediate steps must be taken to minimize permanent brain damage. Although the most common causes of hyperammonemia are severe abnormal liver function, the absence of liver disease in some cases has been observed. This brief report describes four hyperammonemia cases with normal liver function in the ED. On careful history and speculated examinations, ornithine carbamoyltransferase (OTC) deficiency, hematologic malignancy, and the side effects of valproic acid and 5-fluorouracil (5-FU) were considered. Therapy was first aimed at correcting the hyperammonemia. Once a specific diagnosis was reached, protein restriction, essential amino acid supplementation, efficient chemotherapy, and valproic acid and 5-FU level discontinuance were instituted. In this report, the clinical presentation, pathogenesis, and diagnostic workup for various hyperammonemia causes are discussed. Every EP should understand that the clinical symptoms for hyperammonemia and prognosis are related to early diagnosis. (Am J Emerg Med 2004;22:105-107. © 2004 Elsevier Inc. All rights reserved.)
Acute hyperammonemia is a common cause of metabolic encephalopathy found in emergency services. It is a medical emergency for which immediate steps must be taken to minimize permanent brain damage. In adults, it usually appears in diverse situations, including chronic liver disease with portal–systemic shunts and acute fulminant hepatic failure. However, some hyperammonemia occurs in individuals with normal liver function. Other factors must then be considered and corrected. We report on hyperammonemia cases with normal liver function in our ED. CASE REPORTS Case No. 1 A 71-year-old woman came to the ED because of a 1-day history of impaired consciousness. She had experienced several episodes of confusion and drowsiness for the past 10 years. These previous episodes were dramatically and spontaneously resolved with just supportive care alone.
She had hyperthyroidism and had received radioisotope therapy 20 years previously. Her condition was then complicated with hypothyroidism as a result of this treatment. Thyroxine was prescribed and she later attained euthyroid status, besides which her intellectual status was normal. Her two daughters also had hyperthyroidism. No other family health problems were reported. She was disoriented and confused during her physical examination. Her general physical and neurologic examinations were normal. Initial laboratory studies showed a normal complete blood count, coagulation parameters, blood urea nitrogen, creatinine, electrolytes, liver function, glucose, and urine analysis. Ammonia levels rose up to 133 mol/L (normal range, ⬍40 mol/L). Chest x-ray and computed tomography (CT) scan of the head were normal. She became comatose and responsive only to painful stimuli 2 hours after the ED admission. Cleansing enema and lactulose were immediately administered. The patient became vegetative as a result of aspiration pneumonia and hypoxic encephalopathy. Hepatitis markers and abdominal ultrasound failed to show any abnormality. Blood and urine amino acid analysis were performed because all of her common laboratory data were normal. Urinary orotic acid was high (4.6 mol/mmol creatinine, normal, ⬍3.0 mol/mmol creatinine) without protein loading. Plasma amino acid analysis revealed the low level of arginine, whereas plasma levels of citrulline were normal. Allopurinal tests were performed as recommended in women whose medical history is compatible with ornithine carbamoyltransferase (OTC) deficiency.6 Her urinary peak orotidine level was 22.3 mol/mmol creatinine (normal, ⬍ 3.0 mol/mmol creatinine). A diagnosis of partial OTC deficiency was established. A protein-restricted diet, supplemented with essential amino acids to supply the deficient enzyme products arginine and citrulline, was given. Sodium benzoate and sodium phyenyacetate were administered to eliminate ammonia. Her consciousness became clear 1 month later. Case No. 2
From the Department of Emergency Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. Manuscript received March 7, 2003; accepted March 9, 2003. Address reprint requests to Te-I Weng, MD, Department of Emergency Medicine, National Taiwan University Hospital, 7, ChungShan South Road, Taipei, Taiwan. Email: [email protected] Key Words: Hyperammonemia, ED © 2004 Elsevier Inc. All rights reserved. 0735-6757/04/2202-0010$30.00/0 doi:10.1016/j.ajem.2003.12.011
A 70-year-old man with IgA multiple myeloma presented to our ED with a 2-week history of confusion and urinary incontinence. Melphalan and prednisolone chemotherapy medication were administered on an outpatient basis. He was disoriented and confused during the physical examination. His physical examination was normal with no neurologic deficits noted. Initial laboratory tests showed a white blood count of 5700/mm3 hemoglobin (Hb) of 7.6 g/dL, and a platelet count of 11.9 ⫻ 104 mm3. Other results, 105
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AMERICAN JOURNAL OF EMERGENCY MEDICINE ■ Volume 22, Number 2 ■ March 2004
including blood biochemistry, electrolytes, and coagulation studies, were normal. Ammonia was found up to 300 mol/L. Chest x-ray and CT scan of the head were normal. The IgA level remained at approximately 5000 mg/dL. All hepatitis markers were negative. His abdominal ultrasound examination was normal. His consciousness progressed with the improvement in blood ammonia level after lactulose administration. After admission, vincristine, adriamycin, and dexamethasone chemotherapy was given. His consciousness rapidly improved. His bone marrow study showed a decreased amount of myeloma cells, indicating good response to chemotherapy. Case No. 3 A 42-year-old woman presented to the ED because of frequent seizure attacks over a period of 2 days. She had left centrotemporal epilepsy with complex partial and secondary generalized seizures. She was treated with several anticonvulsants, including a combination of valproic acid and phenobarbital. She was lethargic during her physical examination. There was horizontal nystagmus in her lateral gaze. Other examinations were normal. Initial laboratory tests showed normal complete blood count, coagulation parameters, blood urea nitrogen, creatinine, electrolytes, liver function tests, glucose, and urine analysis. Ammonia levels rose to 103 mol/L. Her chest x-ray and CT scan of the head were also normal. Her valproic acid serum concentration was 85 g/mL (therapeutic range; 50-100 g/mL). Her phenobarbital level was 20 g/mL (therapeutic range; 15-40 g/mL). Cleaning enema and lactulose were administrated immediately. An electroencephalogram showed frequent sharp waves in the left centrotemporal region. Two secondary generalized seizures occurred during the examination. Acute valproic acid encephalopathy was suspected. Valproic acid was abruptly discontinued and phenytoin was added. She recovered completely within the next 3 days. At that time, the ammonia concentration was normal. No further seizures occurred during her hospital stay. Case No. 4 A 61-year-old man with gastric cancer presented to our ED with increasing lethargy and sudden confusion. He had advanced gastric cancer with invasion into the adjacent organs. Systemic chemotherapy with 24-hour infusion of high-dose 5-fluorouracil (5-FU) (2600 mg/m2 per week) and leucovorin (300 mg/m2 per week) (HDFL) was administered on an outpatient basis since 1 day before he was brought to our ED. Results of initial neurologic examination were nonfocal, but the patient had alternating periods of lucidity and delirium. Findings on laboratory studies were as follows: complete blood count, coagulation parameters, blood urea nitrogen, creatinine, electrolytes, liver function tests, glucose, and urine analysis were normal. Ammonia levels rose to 500 mol/L. A head CT scan with contrast showed no abnormality. The chemotherapy was immediately discontinued and the patient gradually regained his consciousness 3 hours after discontinuation of 5-FU and folic acid. He was discharged from our ED without any neurologic sequels on the third day.
DISCUSSION Acute hyperammonemia is a medical emergency for which immediate measures must be taken to reduce ammonia levels as fast as possible to minimize permanent brain damage. Measurement of plasma ammonia is a simple but important screening in the ED for patients with unexplained stupor or delirium. Although hyperammonemia can result from diverse disorders, it occurs most frequently in association with seriously impaired liver function. However, of the various diagnostic possibilities, our experience emphasizes the value of prompt hyperammonemia diagnosis and adequate treatment initiation. In case no. 1, we described adult onset of OTC deficiency. OTC deficiency is an X-linked inborn error of urea synthesis.1 OTC is a mitochondrial–matrix enzyme that catalyzes conversion of ornithine and carbamyl phosphate to citrulline, the second step in the urea cycle. OTC deficiency can cause fatal hyperammonemia in male newborns. Heterozygous females might have no symptoms or show a wide variation at onset. The oldest reported patient was a 58-year-old man.2 Our patient experienced the first hyperammonemia episode at the age of 61. The main problem with this disease is hyperammonemia treatment in the ED. Recognizing the symptoms of this disease is often delayed and/or mistaken. The adult onset of abnormal urea cycle metabolism, type II citrullinemia (deficiency of argininosuccinate synthetase [ASS]), and OTC deficiency are common.3 Plasma ammonia measurement is a simple but sensitive screening for urea cycle abnormalities in the ED. The criteria for partial OTC deficiency diagnosis includes one or more of the following: decreased OTC activity in tissue obtained by liver biopsy, episodic hyperammonemia and orotic aciduria in the patient, episodic hyperammonemia in the patient, and orotic aciduria in the patient on oral protein challenge or allopurinol test.4 Plasma amino acid analysis can show low citrulline and arginine levels. An important aspect in late-onset OTC deficiency presentation is that an infection, even as minor as pharyngitis or otitis media, can precipitate hyperammonemia and concomitant clinical decompensation.5 Such an intercurrent illness evokes a protein catabolic response leading to increased ammonia production and the intermittent attacks. Hypercalcemia and hyperviscosity are common causes of encephalopathy in multiple myeloma. A few reports have documented hyperammonemia in patients with hematologic malignancies. Hyperammonemia in multiple myeloma could be caused by (1) the presence of factors that induce hyperammonemia in the patient’s plasma, (2) ammonia production by myeloma cells,6 and (3) formation of a portosystemic shunt resulting from plasma cell infiltration to the liver.7 In case no. 2, the correlation between the myeloma cells and serum ammonia level implied that the primary cause of the hyperammonemia seemed to be ammonia production by the myeloma cells. A peculiar amino acid metabolism has been suggested to exist in myeloma cells, inducing hyperammonemia and serum amino acid disturbance.8 Although valproic acid is generally considered a safe drug, fatal hepatotoxicity has been documented in young children and patients from multiple anticonvulant medica-
WENG ET AL ■ HYPERAMMONEMIA IN THE ED
tions.9 There are also case reports on hyperammonemia secondary to valproic acid therapy in the absence of other liver function abnormalities.10 The typical feature of encephalopathy induced by valproic acid is not dose-dependent like in case no. 3.11 Unless specifically sought, hyperammonemia might be overlooked as a cause of lethargy and ataxia in the postictal patient on valproic acid therapy. In our patient, the ammonia level was elevated without hepatic failure signs. The pathophysiological mechanisms for hyperammonemia include: (1) increased ammonia production in the kidneys by reducing glutamine synthesis; (2) valproic acid metabolites inhibit hepatic urea production by blocking the action of carbamoxyl phosphate synthetase, which is involved in the first step of urea cycle, and (3) hepatic ammonia metabolic reduction from decrement in carnitine availability.12 In case no. 4, we described a patient with 5-FU neurotoxicity manifested as lethargy and confusion. This 5-FUinduced neurotoxicity resulting from hyperammonemia usually presents acute onset and is easily reversible on 5-FU discontinuation.13 The hyperammonemia hypothesis includes the following: the first symptom, complete or incomplete dihydropyrimidine dehydrogenase (DPD) deficiency, and the primary target inactivated by 5-FU. This situation usually results in severe myelosuppression and gastrointestinal toxicity and could be associated with a low level of catabolic products, including ammonia. The second symptom involves treatment accumulation of 5-FU catabolites in large 5-FU doses. The relatively large dose of 5-FU results in transient accumulation of 5-FU catabolites, including ammonia. If 5-FU catabolite disposal, especially ammonia, is not adequate such as with impaired Krebs cycle or malnutrition, transient encephalopathy ensues. The third situation involves a stress situation superimposed on a genetically altered background in the urea cycle.14 In patients with cancer, central nervous system involved with cancer, sepsis, and other metabolis or physical factors might have effects on the consciousness level. Although 24-hour infusion of high-doses of 5-FU and folinic acid have become a popular regimen for many solid tumors, every ED physician should keep in mind that the rare complications by HDFL-related hyperammonemia encephalopathy could develop during or shortly after HDFL administration. After the chemotherapy was discontinued, nearly all patients who experienced hyperammonemia gradually regained consciousness without any sequels.14 A high level of suspicion is necessary to determine the true cause of hyperammonemia, and the prompt initiation of therapies is also vital. If transient severe hyperammonemia
107
develops in the absence of serious liver dysfunction, the patient’s history should be considered carefully. In patients with urea synthesis errors, potentially fatal hyperammonemia can be successfully corrected and controlled.15 Prompt chemotherapy for hematologic malignancies is necessary. Discontinuing valporic acid and 5-FU are important. Therapy aimed at temporarily decreasing the ammonia level such as lactulose, neomycin, hemodialysis, protein restriction, intubation, and controlled ventilation must be considered. The importance of such vigilance and early diagnosis are emphasized by the speed with which severe and even fatal hyperammonemia can occur. REFERENCES 1. Brusilow SW, Horwich AL: Urea cycle enzymes, in Scriver CR, Beaudet AL, Sly WS, et al (eds): The Metabolic Basis of Inherited Disease, 6th ed. New York, McGraw-Hill, 1989, pp 629-663 2. Yoshino M, Nishiyori J, Yamashite F, et al: OTC deficiency in male adolescents and adulthood. Enzyme 1990;43:160-168 3. Kobayashi K, Shaheen N, Jumashiro R, et al: A search for the primary abnormality in adult-onset type II citrullinemia. Am J Hum Genet 1993;53:1024-1030 4. Hauser ER, Finkelstein JE, Valle D, et al: Allopuinol-induced orotidinuria: a test for mutations at the ornithine carbamoyltransferase locus in women. N Engl J Med 1990;322:1641-1645 5. Oppliger-Leibundgut EO, Liechti-Gallati S, Colombo JP, et al: Ornithine transcarbamylase deficiency: new sites with increased probability of mutation. Hum Genet 1995;95:191-196 6. Otsuki T, Yamada O, Sakaguchi H, et al: In vitro excess ammonia production in human myeloma cell lines. Leukemia 1998;12: 1149-1158 7. Takimoto Y, Imanaka F, Hayashi Y, et al: A patient with ammonia-producing multiple myeloma showing hyperammonemic encephalopathy. Leukemia 1996;10:918-919 8. Kwan L, Wang C, Levitt L: Hyperammonemic encephalopathy in multiple myeloma. N Engl J Med 2002;346:1674-1675 9. Rawat S, Borkowski WJ Jr, Swick HM: Valproic acid and secondary hyperammonemia. Neurology 1981;31:1173-1174 10. Zaret BS, Beckner RR, Marini AM, et al: Sodium valproateinduced hyperammonemia without clinical hepatic dysfunction. Neurology 1982;32:206-208 11. Duarte J, Macias S, Coria F, et al: Valproate-induced coma: case report and literature review. Ann Pharmacother 1999;2:582583 12. Thabet H, Brahmi N, Amamou M, et al: A hyperlactatemeia and hyperammonemia as secondary effects of valproic acid poisoning. Am J Emerg Med 2000;18:508 13. Yeh KH, Cheng AL: Acute confusion induced by a high-dose infusion of 5-fluorouracil and folinic acid. J Formos Med Assoc 1994;93:721-723 14. Yeh KH, Cheng AL: High-dose 5-fluorouracil infusional therapy is associated with hyperammonaemia, lactic acidosis and encephalopathy. Br J Cancer 1997;75:464-465 15. Myers JH, Shook JE: Vomiting, ataxia, and altered mental status in an adolescent. Late-onset ornithine transcarbamylase deficiency. Am J Emerg Med 1996;14:553-557
Unusual Causes of Hyperammonemia in the ED TE-I WENG, MD, FRANK FUH-YUAN SHIH, MD, AND WEN-JONE CHEN, MD, PHD Plasma ammonia measurement is a simple yet important screening in the ED for patients with unexplained stupor or delirium. Acute hyperammonemia is a medical emergency for which immediate steps must be taken to minimize permanent brain damage. Although the most common causes of hyperammonemia are severe abnormal liver function, the absence of liver disease in some cases has been observed. This brief report describes four hyperammonemia cases with normal liver function in the ED. On careful history and speculated examinations, ornithine carbamoyltransferase (OTC) deficiency, hematologic malignancy, and the side effects of valproic acid and 5-fluorouracil (5-FU) were considered. Therapy was first aimed at correcting the hyperammonemia. Once a specific diagnosis was reached, protein restriction, essential amino acid supplementation, efficient chemotherapy, and valproic acid and 5-FU level discontinuance were instituted. In this report, the clinical presentation, pathogenesis, and diagnostic workup for various hyperammonemia causes are discussed. Every EP should understand that the clinical symptoms for hyperammonemia and prognosis are related to early diagnosis. (Am J Emerg Med 2004;22:105-107. © 2004 Elsevier Inc. All rights reserved.)
Acute hyperammonemia is a common cause of metabolic encephalopathy found in emergency services. It is a medical emergency for which immediate steps must be taken to minimize permanent brain damage. In adults, it usually appears in diverse situations, including chronic liver disease with portal–systemic shunts and acute fulminant hepatic failure. However, some hyperammonemia occurs in individuals with normal liver function. Other factors must then be considered and corrected. We report on hyperammonemia cases with normal liver function in our ED. CASE REPORTS Case No. 1 A 71-year-old woman came to the ED because of a 1-day history of impaired consciousness. She had experienced several episodes of confusion and drowsiness for the past 10 years. These previous episodes were dramatically and spontaneously resolved with just supportive care alone.
She had hyperthyroidism and had received radioisotope therapy 20 years previously. Her condition was then complicated with hypothyroidism as a result of this treatment. Thyroxine was prescribed and she later attained euthyroid status, besides which her intellectual status was normal. Her two daughters also had hyperthyroidism. No other family health problems were reported. She was disoriented and confused during her physical examination. Her general physical and neurologic examinations were normal. Initial laboratory studies showed a normal complete blood count, coagulation parameters, blood urea nitrogen, creatinine, electrolytes, liver function, glucose, and urine analysis. Ammonia levels rose up to 133 mol/L (normal range, ⬍40 mol/L). Chest x-ray and computed tomography (CT) scan of the head were normal. She became comatose and responsive only to painful stimuli 2 hours after the ED admission. Cleansing enema and lactulose were immediately administered. The patient became vegetative as a result of aspiration pneumonia and hypoxic encephalopathy. Hepatitis markers and abdominal ultrasound failed to show any abnormality. Blood and urine amino acid analysis were performed because all of her common laboratory data were normal. Urinary orotic acid was high (4.6 mol/mmol creatinine, normal, ⬍3.0 mol/mmol creatinine) without protein loading. Plasma amino acid analysis revealed the low level of arginine, whereas plasma levels of citrulline were normal. Allopurinal tests were performed as recommended in women whose medical history is compatible with ornithine carbamoyltransferase (OTC) deficiency.6 Her urinary peak orotidine level was 22.3 mol/mmol creatinine (normal, ⬍ 3.0 mol/mmol creatinine). A diagnosis of partial OTC deficiency was established. A protein-restricted diet, supplemented with essential amino acids to supply the deficient enzyme products arginine and citrulline, was given. Sodium benzoate and sodium phyenyacetate were administered to eliminate ammonia. Her consciousness became clear 1 month later. Case No. 2
From the Department of Emergency Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. Manuscript received March 7, 2003; accepted March 9, 2003. Address reprint requests to Te-I Weng, MD, Department of Emergency Medicine, National Taiwan University Hospital, 7, ChungShan South Road, Taipei, Taiwan. Email: [email protected] Key Words: Hyperammonemia, ED © 2004 Elsevier Inc. All rights reserved. 0735-6757/04/2202-0010$30.00/0 doi:10.1016/j.ajem.2003.12.011
A 70-year-old man with IgA multiple myeloma presented to our ED with a 2-week history of confusion and urinary incontinence. Melphalan and prednisolone chemotherapy medication were administered on an outpatient basis. He was disoriented and confused during the physical examination. His physical examination was normal with no neurologic deficits noted. Initial laboratory tests showed a white blood count of 5700/mm3 hemoglobin (Hb) of 7.6 g/dL, and a platelet count of 11.9 ⫻ 104 mm3. Other results, 105
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AMERICAN JOURNAL OF EMERGENCY MEDICINE ■ Volume 22, Number 2 ■ March 2004
including blood biochemistry, electrolytes, and coagulation studies, were normal. Ammonia was found up to 300 mol/L. Chest x-ray and CT scan of the head were normal. The IgA level remained at approximately 5000 mg/dL. All hepatitis markers were negative. His abdominal ultrasound examination was normal. His consciousness progressed with the improvement in blood ammonia level after lactulose administration. After admission, vincristine, adriamycin, and dexamethasone chemotherapy was given. His consciousness rapidly improved. His bone marrow study showed a decreased amount of myeloma cells, indicating good response to chemotherapy. Case No. 3 A 42-year-old woman presented to the ED because of frequent seizure attacks over a period of 2 days. She had left centrotemporal epilepsy with complex partial and secondary generalized seizures. She was treated with several anticonvulsants, including a combination of valproic acid and phenobarbital. She was lethargic during her physical examination. There was horizontal nystagmus in her lateral gaze. Other examinations were normal. Initial laboratory tests showed normal complete blood count, coagulation parameters, blood urea nitrogen, creatinine, electrolytes, liver function tests, glucose, and urine analysis. Ammonia levels rose to 103 mol/L. Her chest x-ray and CT scan of the head were also normal. Her valproic acid serum concentration was 85 g/mL (therapeutic range; 50-100 g/mL). Her phenobarbital level was 20 g/mL (therapeutic range; 15-40 g/mL). Cleaning enema and lactulose were administrated immediately. An electroencephalogram showed frequent sharp waves in the left centrotemporal region. Two secondary generalized seizures occurred during the examination. Acute valproic acid encephalopathy was suspected. Valproic acid was abruptly discontinued and phenytoin was added. She recovered completely within the next 3 days. At that time, the ammonia concentration was normal. No further seizures occurred during her hospital stay. Case No. 4 A 61-year-old man with gastric cancer presented to our ED with increasing lethargy and sudden confusion. He had advanced gastric cancer with invasion into the adjacent organs. Systemic chemotherapy with 24-hour infusion of high-dose 5-fluorouracil (5-FU) (2600 mg/m2 per week) and leucovorin (300 mg/m2 per week) (HDFL) was administered on an outpatient basis since 1 day before he was brought to our ED. Results of initial neurologic examination were nonfocal, but the patient had alternating periods of lucidity and delirium. Findings on laboratory studies were as follows: complete blood count, coagulation parameters, blood urea nitrogen, creatinine, electrolytes, liver function tests, glucose, and urine analysis were normal. Ammonia levels rose to 500 mol/L. A head CT scan with contrast showed no abnormality. The chemotherapy was immediately discontinued and the patient gradually regained his consciousness 3 hours after discontinuation of 5-FU and folic acid. He was discharged from our ED without any neurologic sequels on the third day.
DISCUSSION Acute hyperammonemia is a medical emergency for which immediate measures must be taken to reduce ammonia levels as fast as possible to minimize permanent brain damage. Measurement of plasma ammonia is a simple but important screening in the ED for patients with unexplained stupor or delirium. Although hyperammonemia can result from diverse disorders, it occurs most frequently in association with seriously impaired liver function. However, of the various diagnostic possibilities, our experience emphasizes the value of prompt hyperammonemia diagnosis and adequate treatment initiation. In case no. 1, we described adult onset of OTC deficiency. OTC deficiency is an X-linked inborn error of urea synthesis.1 OTC is a mitochondrial–matrix enzyme that catalyzes conversion of ornithine and carbamyl phosphate to citrulline, the second step in the urea cycle. OTC deficiency can cause fatal hyperammonemia in male newborns. Heterozygous females might have no symptoms or show a wide variation at onset. The oldest reported patient was a 58-year-old man.2 Our patient experienced the first hyperammonemia episode at the age of 61. The main problem with this disease is hyperammonemia treatment in the ED. Recognizing the symptoms of this disease is often delayed and/or mistaken. The adult onset of abnormal urea cycle metabolism, type II citrullinemia (deficiency of argininosuccinate synthetase [ASS]), and OTC deficiency are common.3 Plasma ammonia measurement is a simple but sensitive screening for urea cycle abnormalities in the ED. The criteria for partial OTC deficiency diagnosis includes one or more of the following: decreased OTC activity in tissue obtained by liver biopsy, episodic hyperammonemia and orotic aciduria in the patient, episodic hyperammonemia in the patient, and orotic aciduria in the patient on oral protein challenge or allopurinol test.4 Plasma amino acid analysis can show low citrulline and arginine levels. An important aspect in late-onset OTC deficiency presentation is that an infection, even as minor as pharyngitis or otitis media, can precipitate hyperammonemia and concomitant clinical decompensation.5 Such an intercurrent illness evokes a protein catabolic response leading to increased ammonia production and the intermittent attacks. Hypercalcemia and hyperviscosity are common causes of encephalopathy in multiple myeloma. A few reports have documented hyperammonemia in patients with hematologic malignancies. Hyperammonemia in multiple myeloma could be caused by (1) the presence of factors that induce hyperammonemia in the patient’s plasma, (2) ammonia production by myeloma cells,6 and (3) formation of a portosystemic shunt resulting from plasma cell infiltration to the liver.7 In case no. 2, the correlation between the myeloma cells and serum ammonia level implied that the primary cause of the hyperammonemia seemed to be ammonia production by the myeloma cells. A peculiar amino acid metabolism has been suggested to exist in myeloma cells, inducing hyperammonemia and serum amino acid disturbance.8 Although valproic acid is generally considered a safe drug, fatal hepatotoxicity has been documented in young children and patients from multiple anticonvulant medica-
WENG ET AL ■ HYPERAMMONEMIA IN THE ED
tions.9 There are also case reports on hyperammonemia secondary to valproic acid therapy in the absence of other liver function abnormalities.10 The typical feature of encephalopathy induced by valproic acid is not dose-dependent like in case no. 3.11 Unless specifically sought, hyperammonemia might be overlooked as a cause of lethargy and ataxia in the postictal patient on valproic acid therapy. In our patient, the ammonia level was elevated without hepatic failure signs. The pathophysiological mechanisms for hyperammonemia include: (1) increased ammonia production in the kidneys by reducing glutamine synthesis; (2) valproic acid metabolites inhibit hepatic urea production by blocking the action of carbamoxyl phosphate synthetase, which is involved in the first step of urea cycle, and (3) hepatic ammonia metabolic reduction from decrement in carnitine availability.12 In case no. 4, we described a patient with 5-FU neurotoxicity manifested as lethargy and confusion. This 5-FUinduced neurotoxicity resulting from hyperammonemia usually presents acute onset and is easily reversible on 5-FU discontinuation.13 The hyperammonemia hypothesis includes the following: the first symptom, complete or incomplete dihydropyrimidine dehydrogenase (DPD) deficiency, and the primary target inactivated by 5-FU. This situation usually results in severe myelosuppression and gastrointestinal toxicity and could be associated with a low level of catabolic products, including ammonia. The second symptom involves treatment accumulation of 5-FU catabolites in large 5-FU doses. The relatively large dose of 5-FU results in transient accumulation of 5-FU catabolites, including ammonia. If 5-FU catabolite disposal, especially ammonia, is not adequate such as with impaired Krebs cycle or malnutrition, transient encephalopathy ensues. The third situation involves a stress situation superimposed on a genetically altered background in the urea cycle.14 In patients with cancer, central nervous system involved with cancer, sepsis, and other metabolis or physical factors might have effects on the consciousness level. Although 24-hour infusion of high-doses of 5-FU and folinic acid have become a popular regimen for many solid tumors, every ED physician should keep in mind that the rare complications by HDFL-related hyperammonemia encephalopathy could develop during or shortly after HDFL administration. After the chemotherapy was discontinued, nearly all patients who experienced hyperammonemia gradually regained consciousness without any sequels.14 A high level of suspicion is necessary to determine the true cause of hyperammonemia, and the prompt initiation of therapies is also vital. If transient severe hyperammonemia
107
develops in the absence of serious liver dysfunction, the patient’s history should be considered carefully. In patients with urea synthesis errors, potentially fatal hyperammonemia can be successfully corrected and controlled.15 Prompt chemotherapy for hematologic malignancies is necessary. Discontinuing valporic acid and 5-FU are important. Therapy aimed at temporarily decreasing the ammonia level such as lactulose, neomycin, hemodialysis, protein restriction, intubation, and controlled ventilation must be considered. The importance of such vigilance and early diagnosis are emphasized by the speed with which severe and even fatal hyperammonemia can occur. REFERENCES 1. Brusilow SW, Horwich AL: Urea cycle enzymes, in Scriver CR, Beaudet AL, Sly WS, et al (eds): The Metabolic Basis of Inherited Disease, 6th ed. New York, McGraw-Hill, 1989, pp 629-663 2. Yoshino M, Nishiyori J, Yamashite F, et al: OTC deficiency in male adolescents and adulthood. Enzyme 1990;43:160-168 3. Kobayashi K, Shaheen N, Jumashiro R, et al: A search for the primary abnormality in adult-onset type II citrullinemia. Am J Hum Genet 1993;53:1024-1030 4. Hauser ER, Finkelstein JE, Valle D, et al: Allopuinol-induced orotidinuria: a test for mutations at the ornithine carbamoyltransferase locus in women. N Engl J Med 1990;322:1641-1645 5. Oppliger-Leibundgut EO, Liechti-Gallati S, Colombo JP, et al: Ornithine transcarbamylase deficiency: new sites with increased probability of mutation. Hum Genet 1995;95:191-196 6. Otsuki T, Yamada O, Sakaguchi H, et al: In vitro excess ammonia production in human myeloma cell lines. Leukemia 1998;12: 1149-1158 7. Takimoto Y, Imanaka F, Hayashi Y, et al: A patient with ammonia-producing multiple myeloma showing hyperammonemic encephalopathy. Leukemia 1996;10:918-919 8. Kwan L, Wang C, Levitt L: Hyperammonemic encephalopathy in multiple myeloma. N Engl J Med 2002;346:1674-1675 9. Rawat S, Borkowski WJ Jr, Swick HM: Valproic acid and secondary hyperammonemia. Neurology 1981;31:1173-1174 10. Zaret BS, Beckner RR, Marini AM, et al: Sodium valproateinduced hyperammonemia without clinical hepatic dysfunction. Neurology 1982;32:206-208 11. Duarte J, Macias S, Coria F, et al: Valproate-induced coma: case report and literature review. Ann Pharmacother 1999;2:582583 12. Thabet H, Brahmi N, Amamou M, et al: A hyperlactatemeia and hyperammonemia as secondary effects of valproic acid poisoning. Am J Emerg Med 2000;18:508 13. Yeh KH, Cheng AL: Acute confusion induced by a high-dose infusion of 5-fluorouracil and folinic acid. J Formos Med Assoc 1994;93:721-723 14. Yeh KH, Cheng AL: High-dose 5-fluorouracil infusional therapy is associated with hyperammonaemia, lactic acidosis and encephalopathy. Br J Cancer 1997;75:464-465 15. Myers JH, Shook JE: Vomiting, ataxia, and altered mental status in an adolescent. Late-onset ornithine transcarbamylase deficiency. Am J Emerg Med 1996;14:553-557