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Postgraduate Education Corner: CONTEMPORARY REVIEWS IN CRITICAL CARE MEDICINE |

Hyperammonemia in the ICU* FREE TO VIEW

Alison S. Clay, MD, FCCP; Bryan E. Hainline, MD
Author and Funding Information

*From the Department of Surgery (Dr. Clay), Duke University School of Medicine, Durham, NC; and the Division of Clinical Biochemical Genetics (Dr. Hainline), Department of Medical and Molecular Genetics, Indiana University School of Medicine, Bloomington, IN.

Correspondence to: Alison S. Clay, MD, FCCP, Department of Surgery and Medicine, Duke University Medical Center, Box 2945, Durham, NC 27710; e-mail: alison.clay@duke.edu



Chest. 2007;132(4):1368-1378. doi:10.1378/chest.06-2940
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Patients experiencing acute elevations of ammonia present to the ICU with encephalopathy, which may progress quickly to cerebral herniation. Patient survival requires immediate treatment of intracerebral hypertension and the reduction of ammonia levels. When hyperammonemia is not thought to be the result of liver failure, treatment for an occult disorder of metabolism must begin prior to the confirmation of an etiology. This article reviews ammonia metabolism, the effects of ammonia on the brain, the causes of hyperammonemia, and the diagnosis of inborn errors of metabolism in adult patients.

Figures in this Article

Patients with acute hyperammonemia have significant morbidity and mortality and are frequently cared for in the ICU. As with many other patients with ailments who seek treatment in the ICU, initial stabilization must focus on treatment, not on diagnosis. Brain edema and intracerebral hypertension must be treated emergently, and ammonia elimination must be facilitated. If acute liver failure is not the cause of hyperammonemia, more unusual causes of acute hyperammonemia must be investigated, such as side effects of certain drugs, infections, or occult disorders of metabolism. Diagnosis, particularly the inborn errors of metabolism (IEMs), often cannot be confirmed until days, or sometimes months, after the initial presentation.

To understand the consequences of, treatments for, and diagnosis of acute hyperammonemia, it is important to review the pathways for the production, metabolism, and excretion of ammonia.

Ammonia metabolism involves primarily five organs—the gut, kidney, muscle, liver, and brain (Fig 1 ). Ammonia is produced mostly in the gut, but also in the kidney and muscle. Within the GI tract, ammonia is a byproduct of protein digestion1and bacterial metabolism.2Within the kidney, ammonia is essential for the renal handling of acid. Ammonium is synthesized from glutamine in the proximal tubule and ultimately is concentrated in the medullary interstitium,3where it is either released into the systemic circulation or used to facilitate the excretion of protons. Renal ammonia production is dynamic and increases with alterations in renal acid-base status changes and with GI bleeding.45 Finally, skeletal muscle can also produce ammonia, usually during seizures or with intense exercise.1

The liver is primarily responsible for ammonia degradation. Ammonia in the venous system (which is produced by the digestion of protein in the splanchnic circulation and by muscle peripherally) is metabolized to urea through the urea cycle (Fig 2 ). Several enzymes are required for the urea cycle, including the rate-limiting enzyme carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinic acid lyase, and arginase. Arginine is necessary for urea cycle function and is a quasi-essential amino acid when dietary nitrogen intake is insufficient or when a defect in the urea cycle is present. Because venous ammonia levels vary locally and because the liver is so adept at the metabolism of ammonia, arterial ammonia levels usually do not correlate with venous ammonia levels.69

When the capacity of the liver to metabolize ammonia is overcome, either because ammonia production exceeds the metabolic capacity of the liver or because the liver is unable to metabolize ammonia, elimination is dependent on the kidney, muscle, and brain. In the setting of hyperammonemia, the kidney decreases ammonia production and increases urinary excretion of ammonia.4,10 The muscle46,1112 and brain metabolize excess ammonia to glutamine.1,1113 The process of metabolizing ammonia to glutamine is physiologically costly, particularly in the brain where the symbiotic relationship between neurons and astrocytes is disrupted by excess glutamine production.

Under normal physiologic conditions, astrocytes support adjacent neurons with adenosine 5′-triphosphate, glutamine, and cholesterol. The neuron metabolizes glutamine to glutamate, which is a neurotransmitter that activates N-methyl D-aspartic acid receptors. After release into the synapse, glutamate is recycled by the astrocyte to glutamine, resulting in the functional compartmentalization of glutamate and glutamine. When ammonia levels rise acutely within the brain, astrocyte and neuron function are affected. Astrocytes rapidly metabolize ammonia to glutamine, but the subsequent rise in intracellular osmolarity causes astrocyte swelling and loss.1,1113 Inflammatory cytokines, including tumor necrosis factor-α, interleukin-1, interleukin-6 and interferon, are released by the astrocyte.13 Ongoing oxidative and nitrosative stress cause additional astrocyte loss through apoptosis.12 In the remaining astrocytes, ammonia-mediated inhibition of alpha-ketoglutarate dehydrogenase and the depletion of carboxylic acids for glutamine synthesis paralyzes the Krebs cycle.1,11,1314 Adenosine 5′-triphosphate and nicotinamide adenine dinucleotide (reduced form) production fall,1,11,1314 and rising nicotinamide adenine dinucleotide (oxidized form) favors the metabolism of pyruvate to lactate.15 Lactate levels in the astrocyte and brain increase.13 Decreased expression of glutamate receptors in astrocytes cause increased concentrations of glutamate,1,1114 and seizures may result. Cerebral blood flow increases,1,12 effective cerebral autoregulation is lost,1213 and cerebral edema and intracranial hypertension (ICH) may develop.1

Cerebral edema and herniation (as well as seizures) are unique to acute hyperammonemia and usually occur only when arterial ammonia levels are > 200 μmol/L.1213 The rise in ammonia levels, the elevations of glutamine, and the effect of glutamine on the brain are proposed to account for the different effects of acute (vs chronic) hyperammonemia on the brain. In patients with chronic hyperammonemia, ammonia is metabolized more efficiently by muscles and the hepatic-splanchnic beds.7 Ammonia also has a less pronounced chronic effect on the brain as follows: osmolarity does not rise as an acutely; down-regulation of N-methyl D-aspartic acid receptors results in less neuroexcitation from glutamate11,14; and ammonia has more of an effect on neuroinhibitory gamma aminobutyric acid receptors.13

Although venous, arterial, and brain ammonia levels do not usually correlate, acute hyperammonemia may be an exception. In patients with fulminant hepatic failure, venous ammonia levels correlate with arterial ammonia levels.9 In addition, arterial ammonia levels may be predictive of what is happening in the brain, as follows: arterial ammonia levels in patients with fulminant hepatic failure correlate with glutamine levels, which correlate with the development of ICH.7,9,1617

Several treatments are appropriate for all patients with hyperammonemia, while some treatments are reserved for those with hyperammonemia that is thought to be related to an IEM (Table 1 ). Often, therapy must be given empirically, as the diagnosis of IEM can take weeks to months.

For both types of patients, initial treatment must focus on the management of ICH, which is a condition that is associated with increased morbidity and mortality.18 Usually, hyperammonemia in adults is associated with cerebral edema, decreased cerebral metabolism, and increases in cerebral blood flow. The management of these patients entails the reduction of cerebral edema and cerebral blood flow.18 However, in some patients cerebral blood flow may be reduced; in these patients, drugs that lower cerebral blood flow and cerebral perfusion pressure must be avoided.18Unfortunately, placement of intracranial pressure monitoring is associated with complications,19 and management may need to be performed empirically. Given the dynamic changes in cerebral blood flow, there is controversy about which management strategy is most appropriate.

Hypothermia12,18,20 abrogates many of the metabolic effects of ammonia, as follows: decreasing free radical production,13 astrocyte swelling, and inflammation; while improving cerebral blood flow and autoregulation. Hypothermia also slows protein catabolism and the production of ammonia by bacteria and the kidney.20 Hypothermia is the least controversial of treatments. N-acetylcysteine may reduce cerebral edema and cerebral metabolism; as a result, N-acetylcysteine may be beneficial even in the absence of acetaminophen toxicity.18 Although mannitol may increase the influx of ammonia across the blood-brain barrier in canines,21 mannitol administration in humans has been shown to reduce cerebral edema and improve mortality.18,22 Two additional controversial treatments include the following: the use of indomethacin, which reduces inflammation and decreases cerebral blood flow but which may cause renal failure12,18,23; and propofol, which successfully sedates patients and decreases cerebral blood flow24 but which may be harmful in patients without adequate cerebral perfusion pressures.

In addition to therapies that treat ICH, additional supportive therapy is recommended. Because up to 40% of patients with hyperammonemia and elevated intracranial pressure have subclinical seizures,12,25 therapy with dilantin or phenobarbital should be considered.18,25Lactulose, a main stay of treatment in patients with chronic hyperammonemia,26 has not been shown to affect mortality in patients with acute hyperammonemia, but it is unlikely to be harmful.18 Antibiotics and antifungal agents can treat underlying infection and may prevent superinfection in these immunocompromised patients.2728 Nutritional support must be provided to prevent protein catabolism. Protein intake must be stopped; normal or supranormal caloric intake may be provided with dextrose and lipids. Once the patient is sufficiently stable to be fed enterally, a protein-free enteral formula (eg, Pro-Phree; Abbott Nutrition; Columbus, OH; or PFD 1 or 2 [formerly known as 80056]; Mead Johnson; Evansville, IN) should be provided.

If ammonia levels remain at > 100 μmol/L and/or the etiology of hyperammonemia remains elusive, an IEM may be present. For these patients, additional therapies are useful to reduce ammonia levels, by actively removing ammonia, facilitating its metabolism, and by decreasing its production (Fig 3 ). A multifaceted approach can have a dramatic effect on serum ammonia levels (Fig 4 ).

Peritoneal dialysis,2930 hemodialysis,2932 continuous venovenous hemofiltration,29,3334 continuous venovenous hemodiafiltration,35and continuous arteriovenous hemodiafiltration36 are effective ways to remove ammonia and have been helpful in treating hyperammonemia associated with urea cycle disorders in children and adults. These interventions could serve as a potential bridge for adults with fulminant hepatic failure who are awaiting transplantation.

Nitrogen elimination may also be accomplished through pharmacologic manipulation31,3741(Fig 3). Sodium phenylacetate and sodium benzoate promote the degradation of ammonia through “alternate” metabolic pathways. The side effects of these medications, which are administered IV, include nausea, vomiting, and hypokalemia.39In some cases of acute hyperammonemia, the use of these agents has prevented the need for dialysis.4041 When dialysis is used in conjugation with these medications, the drugs should be dosed after dialysis.34 Treatment with these agents must often begin before a diagnosis is confirmed. Although these drugs have a hypothetical benefit for all patients with hyperammonemia, they have been approved by the US Food and Drug Administration only for the treatment of hyperammonemic crisis in patients with IEMs. IV arginine administration may also promote nitrogen excretion by preventing protein catabolism, especially in patients with diseases in which in vivo synthesis of arginine is limited by enzyme deficiencies.,41L-carnitine facilitates lipid metabolism, and may reduce cerebral lactate levels by indirectly stimulating pyruvate dehydrogenase.42

Liver transplantation has been used successfully for cirrhosis and fulminant hepatic failure (whether from drug induced, viral, autoimmune, or cryptogenic)4344 as well as for disorders of the metabolism, including citrullinemia,4548 OTC deficiency,31,45,49 and CPS deficiency.31,48

After instituting measures to stabilize the patient and to reduce the risk of herniation, a diagnostic evaluation should begin. The causes of hyperammonemia can be divided into processes that increase ammonia production or decrease ammonia elimination (Table 2 ).

Several processes result in increased ammonia production. The metabolism of protein increases blood ammonia levels and can be seen with total parenteral nutrition (TPN),5051 GI hemorrhage,52 steroid use,21 trauma,21 and GI hemorrhage.5 Other conditions can also increase ammonia production, such as infection with urease-splitting organisms,5357 herpes infection,58 urinary diversion,54,5961 or multiple myeloma.31,6267

Decreased ammonia elimination is seen in the setting of fulminant hepatic failure, portosystemic shunting, drug administration, or IEM. Fulminant hepatic failure is the most common cause of acute hyperammonemia in adult ICUs, with about 2,000 cases annually.44 In a prospective study68 of acute liver failure at 17 US tertiary care centers, acetaminophen toxicity accounted for 39% of cases, drug reactions for 13% of cases, viral hepatitis (A or B) for 12% of cases, and idiopathic causes for 17% of cases. Additional causes of fulminant hepatic failure include the following: infections (eg, the hepatitides, varicella, Epstein-Barr virus, and cytomegalovirus); drugs (Table 2); autoimmune diseases; vascular diseases (eg, Budd-Chiari and venoocclusive disease); pregnancy-related conditions (eg, acute fatty liver of pregnancy, and eclampsia); and toxins (eg, mushrooms and herbs).,4344

Several drugs cause hyperammonemia by disrupting the urea cycle. Glycine, which is used during transurethral resection of the prostate, stimulates ammonia production.69Salicylates can reduce mitochondrial function in the liver as is suggested to occur with Reye syndrome.7071 Valproate increases propionic acid levels, which inhibit CPS. As a result, an overdose with valproate may cause marked hyperammonemia in healthy patients,31,72 while therapeutic doses of valproate may cause hyperammonemic coma in patients with underlying urea cycle disorder (UCD).31,7382 Although the mechanisms are not known, case reports have also described hyperammonemia after the use of carbamazepine,8384 ribavirin,85and sulfadiazine with pyrimethamine.86

IEMs may also cause hyperammonemia,31,87 including defects in the β-oxidation of fatty acids causing carnitine deficiency, organic acidurias, and UCDs. Most severe IEMs present early in childhood. However, UCDs may present in adulthood when they are unmasked by precipitants such as increased protein intake, drugs, or infection. The prevalence if UCDs is estimated at 1 in 25,000 cases to 1 in 30,000 cases.31,37,88 The most common UCDs diagnosed in adults are OTC deficiency, ASS deficiency, and carbamyl phosphate deficiency.

OTC deficiency is the most common UCD discovered in adults. OTC deficiency is a X-linked disease usually presenting in male infants,37,89 or rarely in adolescents.8992 However, the carrier ratio in women is approximately 1:70. In female heterozygotes, random inactivation (lyonization) of the X chromosome within each hepatocyte results in phenotypic variation. As a result, clinical manifestations of OTC do not develop in many female patients until they are adults.50,7778,89,93100

CPS deficiency, an autosomal-recessive disease,101 may also present in adulthood.82,101108 At least 14 mutations have been described in the CPS gene.109Deficiency of N-acetyl glutamine synthetase (NAGS) mimics CPS deficiency110because N-acetyl glutamine is an essential allosteric activator of CPS I. Although complete NAGS deficiency usually presents in children,111 patients with hypomorphic alleles may present in adulthood if their partially functional enzyme is inhibited by short-chain fatty acids or treatment with valproic acid.111114 Partial NAGS deficiency may be more common than previously thought.112

ASS deficiency, also called citrullinemia due to the accumulation of citrulline, has an incidence of approximately 1 case per 70,000 to 100,000 cases.37,115116 There are two types of recessively inherited ASS deficiency, one that presents in infants (type I) and one that presents in adults (type II). Type II citrullinemia, which is characterized by a genetic mutations in the citrin gene, affects the expression of ASS within the liver.115 Nearly 50% of patients with type II ASS deficiency present in their 20s or early 30s, usually with psychiatric manifestations.46,115119 In most patients with type II ASS deficiency, the disease progresses to death from cirrhosis within years after the onset of hyperammonemia47,115116 unless liver transplantation is undertaken.

Other inherited disorders of metabolism that may present with hyperammonemia in adulthood include hyperammonemia-hyperornithinemia- homocitrullinuria (HHH)37,120123 and lysinuric protein intolerance.37,124127 Neither of these diseases is a UCD, but both impair the utilization of ornithine, causing functional impairment of the urea cycle.121,125 HHH is an autosomal-recessive disease that is characterized by defective ornithine transport across the inner mitochondrial membrane.121 The disease is characterized by neurologic deficits, including spastic paresis, ataxia, seizures, and mental retardation.121,128Patients with HHH may present with acute liver disease and coagulopathy.129 Lysinuric protein intolerance is a disease with defective dibasic amino acid transport. Patients have protein intolerance, osteoporosis, interstitial lung disease, and focal segmental glomerulosclerosis,124125,130 and an autoimmune disease with hemolytic anemia that mimics systemic lupus erythematosus may develop.130

Although there are multiple UCDs, their clinical presentations are quite similar. In the fulminant form, patients present with coma and encephalopathy, while in the milder forms of the disease patients often have intermittent periods of confusion or bizarre behavior, presumably from hyperammonemia.31,37,46,50,78,80,88,90,93,101,105,115,117119 Many patients have seizure disorders, including partial complex seizures, which may explain their occasional confusion.37,46,77,88,90,94 A history of repetitive or cyclical vomiting may be present.29,31,34,38,46,77,8081,88,90,93,101102,105,125 Patients may have intellectual limitations such as learning disabilities or mild mental retardation.37,77,101 Patients may voluntarily limit their protein intake (called auto-vegetarianism) to avoid postprandial headaches or somnolence.,31,3738,50,77,90,93,108,121,124,129130 Patients with citrullinemia (ie, ASS deficiency) often have a history of preferring beans, presumably because beans provide arginine, which is an essential amino acid, in these patients.,37,46,115

Physiologic stressors that provoke hyperammonemia in patients with these metabolic disorders include the following: upper respiratory tract illnesses102; pneumonia115; dietary changes; fever90; pregnancy36,78,96,108; GI bleeding52,59; and infection with urease-splitting organisms.5457 Insults to the liver, such as alcohol or acetaminophen, can provoke or worsen hyperammonemia in a susceptible patient.115 TPN, which often provides more protein than the patient usually consumes enterally, has provoked hyperammonemia in many patients with UCDs, most often OTC.50,78 The presence of hyperammonemia following TPN should prompt an investigation of a UCD.

One final cause of hyperammonia is idiopathic hyperammonemia (IHA), a clinical condition in which elevated ammonia levels are disproportionate to liver dysfunction in the absence of an inherited metabolic disorder. IHA was first described as a complication of intensive chemotherapy in leukemia patients but has subsequently been described in patients undergoing bone marrow transplantation, in patients with solid tumors treated with continuous infusions of 5-fluorouracil,131136 and in patients after lung transplantation.137 The mortality rate exceeds 75% in the reported cases. The incidence is unknown, but in previous retrospective reviews131,134 was estimated to range from 0.5 to 2.4%. The etiology of IHA is not known; although some investigators134 have postulated transient abnormalities in urea synthesis. Others138 have suggested that the increased production of ammonia present in these patients occurs from tissue breakdown, mucositis, and GI bleeding. Those patients who have survived IHA were identified and treated exceptionally early with ammonia-trapping agents and dialysis.

The search for the source of hyperammonemia should initially focus on fulminant hepatic failure and then progress to a workup for IEM if the hyperammonemia cannot be explained (Table 1). In addition to liver function and coagulation tests, the measurement of acetaminophen levels, alcohol/drug toxicology, and viral serologies for the hepatitides should be drawn.43 A careful medication and social history should be obtained to rule out drug-induced acute liver failure.43 Ultrasound should be performed to rule out portal vein thrombosis and fatty infiltration. Abdominal CT scanning may be helpful.

The presence of infection, increased protein catabolism, or drug administration should be evaluated. If the degree of hyperammonemia is inconsistent with one of these diagnoses or they are ruled out, the physician should also consider an occult UCD. In UCD, routine blood chemistry measurement and liver function test results may be abnormal, including elevations of transaminase levels and mild elevations of indirect bilirubin levels,31,38,47,78,115,118,129,139 coagulopathy,31,47,78,118 respiratory alkalosis,103,139 and metabolic acidosis (sometimes with an elevated anion gap).118

To evaluate further for a suspected IEM, quantitative plasma and urine amino acids (including citrulline, argininosuccinic acid, and glutamine), urine organic acid analysis, urine orotic acid, and carnitine should be obtained.31,37,140141 Specimens used for these analyses should be sent to the laboratory on ice to prevent spurious results.31 Falsely low glutamine levels can limit the diagnostic evaluation. A diagnostic algorithm is provided to aid the interpretation of these test results (Fig 5 ).

When an IEM is suspected, liver biopsy should be considered to confirm the diagnosis. A biopsy must be undertaken with caution to prevent a hyperammonemic episode. Mutation analysis may be performed utilizing DNA derived from blood lymphocytes. However, because of the high frequency of genetic polymorphisms in large genes, genetic confirmation of the disease may not be possible until the expression of the presumed mutations is undertaken in vitro or in vivo model systems.142 At present, genetic testing is routinely available only for OTC deficiency.141

Although the UCD disorders are rare, diagnosis is important. Reducing ammonia levels quickly and preventing future episodes of hyperammonemia can prevent death and neurologic deterioration.37,3940,143145 Early recognition of these diseases may also help to prevent consequences for other patients or family members. A liver transplant recipient146147 died from hyperammonemia after receiving an organ from an adult male patient who had died of cerebral edema of unknown etiology. Subsequent studies146147 revealed OTC deficiency in the donor. Incidents such as this are a reminder that the true prevalence of inherited metabolic disorders such as UCDs cannot be known until they are readily identified and diagnosed in adulthood.

Hyperammonemia with altered mental status often requires treatment by an intensivist. The effects of hyperammonemia on the brain are significant and often fatal. Early management of cerebral hypertension is essential. When ammonia levels are disproportionate to the degree of liver function or when no obvious cause for hyperammonemia can be immediately identified, intervention may also require empiric management for IEM.

Abbreviations: ASS = argininosuccinate synthetase; CPS = carbamyl phosphate synthetase; HHH = hyperammonemia-hyperornithinemia-homocitrullinuria; ICH = intracranial hypertension; IEM = inborn error of metabolism; IHA = idiopathic hyperammonemia; NAGS = N-acetyl glutamine synthetase; OTC = ornithine transcarbamylase; TPN = total parenteral nutrition; UCD = urea cycle disorder

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Figure Jump LinkFigure 1. Organs responsible for ammonia metabolism.Grahic Jump Location
Table Graphic Jump Location
Table 1. Evaluation and Treatment of Hyperammonemia*
* 

TURP = transurethral resection of the prostate; SIRS = systemic inflammatory response syndrome; EBV = Epstein-Barr virus; TB = tuberculosis; CMV = cytomegalovirus.

Figure Jump LinkFigure 4. Response to treatment. CVVHD = continuous venovenous hemodiafiltration; HD = hemodiafiltration.Grahic Jump Location
Table Graphic Jump Location
Table 2. Causes of Hyperammonemia in Adults*
* 

TIPSS = transjugular intrahepatic portosystemic shunt.

Figure Jump LinkFigure 5. Diagnostic algorithm for UCD. ASA = acetylsalicylic acid.Grahic Jump Location
Table Graphic Jump Location
Table 3. Drugs Associated With Hyperammonemia*
* 

MDMA = 3,4 methylenedioxymethamphetamine.

Bachmann, C (2002) Mechanisms of hyperammonemia.Clin Chem Lab Med40,653-662. [PubMed] [CrossRef]
 
Vince, A, Dawson, AM, Park, N, et al Ammonia production by intestinal bacteria.Gut1973;14,171-177. [PubMed]
 
Karim, Z, Szutkowska, M, Vernimmen, C, et al Renal handling of NH3/NH4+: recent concepts.Nephron Physiol2005;101,77-81
 
Olde Damink, SW, Dejong, CH, Deutz, NE, et al Kidney plays a major role in ammonia homeostasis after portasystemic shunting in patients with cirrhosis.Am J Physiol Gastrointest Liver Physiol2006;291,G189-G194. [PubMed]
 
Olde Damink, SW, Dejong, CH, Deutz, NE, et al Upper gastrointestinal bleeding: an ammoniagenic and catabolic event due to the total absence of isoleucine in the haemoglobin molecule.Med Hypotheses1999;52,515-519. [PubMed]
 
Clemmesen, JO, Kondrup, J, Ott, P Splanchnic and leg exchange of amino acids and ammonia in acute liver failure.Gastroenterology2000;118,1131-1139. [PubMed]
 
Clemmesen, JO, Larsen, FS, Kondrup, J, et al Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration.Hepatology1999;29,648-653. [PubMed]
 
Lockwood, AH Blood ammonia levels and hepatic encephalopathy.Metab Brain Dis2004;19,345-349. [PubMed]
 
Ong, JP, Aggarwal, A, Krieger, D, et al Correlation between ammonia levels and the severity of hepatic encephalopathy.Am J Med2003;114,188-193. [PubMed]
 
Olde Damink, SW, Jalan, R, Duetz, N, et al The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis.Hepatology2003;37,1277-1285. [PubMed]
 
Butterworth, RF Effects of hyperammonaemia on brain function.J Inherit Metab Dis1998;21,6-20. [PubMed]
 
Vaquero, J, Chung, C, Cahill, ME, et al Pathogenesis of hepatic encephalopathy in acute liver failure.Semin Liver Dis2003;23,259-269. [PubMed]
 
Shawcross, D, Jalan, R The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.Cell Mol Life Sci2005;62,2295-2304. [PubMed]
 
Butterworth, RF Glutamate transporter and receptor function in disorders of ammonia metabolism.Ment Retard Dev Disabil Res Rev2001;7,276-279. [PubMed]
 
Ott, P, Clemmesen, O, Larsen, FS Cerebral metabolic disturbances in the brain during acute liver failure: from hyperammonemia to energy failure and proteolysis.Neurochem Int2005;47,13-18. [PubMed]
 
Strauss, GI, Knudsen, GM, Kondrup, J, et al Cerebral metabolism of ammonia and amino acids in patients with fulminant hepatic failure.Gastroenterology2001;121,1109-1119. [PubMed]
 
Tofteng, F, Hauerberg, J, Hansen, B, et al Persistent arterial hyperammonemia increases the concentration of glutamine and alanine in the brain and correlates with intracranial pressure in patients with fulminant hepatic failure.J Cereb Blood Flow Metab2006;26,21-27. [PubMed]
 
Jalan, R Intracranial hypertension in acute liver failure: pathophysiological basis of rational management.Semin Liver Dis2003;23,271-282. [PubMed]
 
Blei, AT, Olafsson, S, Webster, S, et al Complications of intracranial pressure monitoring in fulminant hepatic failure.Lancet1993;341,157-158. [PubMed]
 
Vaquero, J, Blei, AT Mild hypothermia for acute liver failure: a review of mechanisms of action.J Clin Gastroenterol2005;39,S147-S157. [PubMed]
 
Summar, M, Barr, F, Dawling, S, et al Unmasked adult-onset urea cycle disorders in the critical care setting.Crit Care Clin2005;21(suppl),S1-S8
 
Canalese, J, Gimson, A, Davis, C Controlled trial of dexamethasone and mannitol for cerebral oedema of fulminant hepatic failure.Gut1982;23,625-629. [PubMed]
 
Clemmesen, J, Hansen, B, Larsen, FS Indomethacin normalizes intracranial pressure in acute liver failure: a twenty-three year old woman treated with indomethacin.Hepatology1997;26,1423-1425. [PubMed]
 
Wijdicks, EF, Nyberg, SL Propofol to control intracranial pressure in fulminant hepatic failure.Transplant Proc2002;34,1220-1222. [PubMed]
 
Ellis, A, Wendon, J, Williams, R Subclinical seizure activity and prophylactic phenytoin infusion in acute liver failure: a controlled clinical trial.Hepatology2000;38,536-541
 
Watanabe, A, Sakai, T, Sato, S, et al Clinical efficacy of lactulose in cirrhotic patients with and without subclinical hepatic encephalopathy.Hepatology1997;26,1410-1414. [PubMed]
 
Rolando, N, Gimson, A, Wade, J, et al Prospective controlled trial of selective parenteral and enteral antimicrobial regimen in fulminant liver failure.Hepatology1993;17,196-201. [PubMed]
 
Rolando, N, Harvey, F, Brahm, J, et al Fungal infection: a common, unrecognised complication of acute liver failure.J Hepatol1991;12,1-9. [PubMed]
 
Chang, MY, Fang, JT, Chen, YC, et al Continuous venovenous haemofiltration in hyperammonaemic coma of an adult with non-diagnosed partial ornithine transcarbamylase deficiency.Nephrol Dial Transplant1999;14,1282-1284. [PubMed]
 
Donn, SM, Swartz, RD, Thoene, JG Comparison of exchange transfusion, peritoneal dialysis, and hemodialysis for the treatment of hyperammonemia in an anuric newborn infant.J Pediatr1979;95,67-70. [PubMed]
 
Treem, WR Inherited and acquired syndromes of hyperammonemia and encephalopathy in children.Semin Liver Dis1994;14,236-258. [PubMed]
 
Rutledge, SL, Havens, PL, Haymond, MW, et al Neonatal hemodialysis: effective therapy for the encephalopathy of inborn errors of metabolism.J Pediatr1990;116,125-128. [PubMed]
 
Falk, MC, Knight, JF, Roy, LP, et al Continuous venovenous haemofiltration in the acute treatment of inborn errors of metabolism.Pediatr Nephrol1994;8,330-333. [PubMed]
 
Mathias, RS, Kostiner, D, Packman, S Hyperammonemia in urea cycle disorders: role of the nephrologist.Am J Kidney Dis2001;37,1069-1080. [PubMed]
 
Summar, M, Pietsch, J, Deshpande, J, et al Effective hemodialysis and hemofiltration driven by an extracorporeal membrane oxygenation pump in infants with hyperammonemia.J Pediatr1996;128,379-382. [PubMed]
 
Wong, KY, Wong, SN, Lam, SY, et al Ammonia clearance by peritoneal dialysis and continuous arteriovenous hemodiafiltration.Pediatr Nephrol1998;12,589-591. [PubMed]
 
Brusilow, S, Horwich, A Urea cycle enzymes. 8th ed.2001 McGraw-Hill. New York, NY:
 
Mizutani, N, Maehara, M, Hayakawa, C, et al Hyperargininemia: clinical course and treatment with sodium benzoate and phenylacetic acid.Brain Dev1983;5,555-563. [PubMed]
 
Batshaw, ML, MacArthur, RB, Tuchman, M Alternative pathway therapy for urea cycle disorders: twenty years later.J Pediatr2001;138,S46-S54. [PubMed]
 
Brusilow, SW, Danney, M, Waber, LJ, et al Treatment of episodic hyperammonemia in children with inborn errors of urea synthesis.N Engl J Med1984;310,1630-1634. [PubMed]
 
Brusilow, SW Arginine, an indispensable amino acid for patients with inborn errors of urea synthesis.J Clin Invest1984;74,2144-2148. [PubMed]
 
Malaguarnera, M, Pistone, G, Astuto, M, et al L-Carnitine in the treatment of mild or moderate hepatic encephalopathy.Dig Dis2003;21,271-275. [PubMed]
 
Rahman, T, Hodgson, H Clinical management of acute hepatic failure.Intensive Care Med2001;27,467-476. [PubMed]
 
Sass, DA, Shakil, AO Fulminant hepatic failure.Liver Transpl2005;11,594-605. [PubMed]
 
Jan, D, Laurent, J, Lacaille, F, et al Liver transplantation in children with inherited metabolic disorders.Transplant Proc1995;27,1706-1707. [PubMed]
 
Ikeda, S, Yazaki, M, Takei, Y, et al Type II (adult onset) citrullinaemia: clinical pictures and the therapeutic effect of liver transplantation.J Neurol Neurosurg Psychiatry2001;71,663-670. [PubMed]
 
Yazaki, M, Ikeda, S, Takei, Y, et al Complete neurological recovery of an adult patient with type II citrullinemia after living related partial liver transplantation.Transplantation1996;62,1679-1684. [PubMed]
 
Todo, S, Starzl, TE, Tzakis, A, et al Orthotopic liver transplantation for urea cycle enzyme deficiency.Hepatology1992;15,419-422. [PubMed]
 
Largilliere, C, Houssin, D, Gottrand, F, et al Liver transplantation for ornithine transcarbamylase deficiency in a girl.J Pediatr1989;115,415-417. [PubMed]
 
Felig, DM, Brusilow, SW, Boyer, JL Hyperammonemic coma due to parenteral nutrition in a woman with heterozygous ornithine transcarbamylase deficiency.Gastroenterology1995;109,282-284. [PubMed]
 
Benque, A, Bommelaer, G, Rosental, G Chronic vomiting in a case of citrullinaemia detected after treatment by total parenteral nutrition.Gut1984;25,531-533. [PubMed]
 
Trivedi, M, Zafar, S, Spalding, MJ, et al Ornithine transcarbamylase deficiency unmasked because of gastrointestinal bleeding.J Clin Gastroenterol2001;32,340-343. [PubMed]
 
Cheang, HK, Rangecroft, L, Plant, ND, et al Hyperammonaemia due to Klebsiella infection in a neuropathic bladder.Pediatr Nephrol1998;12,658-659. [PubMed]
 
Kaveggia, FF, Thompson, JS, Schafer, EC, et al Hyperammonemic encephalopathy in urinary diversion with urea-splitting urinary tract infection.Arch Intern Med1990;150,2389-2392. [PubMed]
 
Laube, GF, Superti-Furga, A, Losa, M, et al Hyperammonaemic encephalopathy in a 13-year-old boy.Eur J Pediatr2002;161,163-164. [PubMed]
 
Zuberi, SM, Stephenson, JB, Azmy, AF, et al Hyperammonaemic encephalopathy after a subureteric injection for vesicoureteric reflux.Arch Dis Child1998;79,363-364. [PubMed]
 
Samtoy, B, DeBeukelaer, MM Ammonia encephalopathy secondary to urinary tract infection withProteus mirabilis.Pediatrics1980;65,294-297. [PubMed]
 
Barnes, PM, Wheldon, DB, Eggerding, C, et al Hyperammonaemia and disseminated herpes simplex infection in the neonatal period.Lancet1982;1,1362-1363
 
Hawkes, ND, Thomas, GA, Jurewicz, A, et al Non-hepatic hyperammonaemia: an important, potentially reversible cause of encephalopathy.Postgrad Med J2001;77,717-722. [PubMed]
 
Cascino, GD, Jensen, JM, Nelson, LA, et al Periodic hyperammonemic encephalopathy associated with a ureterosigmoidostomy.Mayo Clin Proc1989;64,653-656. [PubMed]
 
Gilbert, GJ Acute ammonia intoxication 37 years after ureterosigmoidostomy.South Med J1988;81,1443-1445. [PubMed]
 
Matsuzaki, H, Uchiba, M, Yoshimura, K, et al Hyperammonemia in multiple myeloma.Acta Haematol1990;84,130-134. [PubMed]
 
Fine, P, Adler, K, Gerstenfeld, D Idiopathic hyperammonemia after high-dose chemotherapy.Am J Med1989;86,629
 
Perez Retortillo, JA, Marco, F, Amutio, E, et al Hyperammonemic encephalopathy in multiple myeloma.Haematologica1998;83,956-957. [PubMed]
 
Kwan, L, Wang, C, Levitt, L Hyperammonemic encephalopathy in multiple myeloma.N Engl J Med2002;346,1674-1675
 
Takimoto, Y, Imanaka, F, Hayashi, Y, et al A patient with ammonia-producing multiple myeloma showing hyperammonemic encephalopathy.Leukemia1996;10,918-919. [PubMed]
 
Keller, DR, Keller, K Hyperammonemic encephalopathy in multiple myeloma.Am J Hematol1998;57,264-265. [PubMed]
 
Ostapowicz, G, Fontana, RJ, Schiodt, FV, et al Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States.Ann Intern Med2002;137,947-954. [PubMed]
 
Ryder, KW, Olson, JF, Kahnoski, RJ, et al Hyperammonemia after transurethral resection of the prostate: a report of 2 cases.J Urol1984;132,995-997. [PubMed]
 
DeLong, GR, Glick, TH Ammonia metabolism in Reye syndrome and the effect of citrulline.Ann Neurol1982;11,53-58. [PubMed]
 
Makela, AL, Lang, H, Korpela, P Toxic encephalopathy with hyperammonaemia during high-dose salicylate therapy.Acta Neurol Scand1980;61,146-156. [PubMed]
 
Kulick, SK, Kramer, DA Hyperammonemia secondary to valproic acid as a cause of lethargy in a postictal patient.Ann Emerg Med1993;22,610-612. [PubMed]
 
Verrotti, A, Greco, R, Morgese, G, et al Carnitine deficiency and hyperammonemia in children receiving valproic acid with and without other anticonvulsant drugs.Int J Clin Lab Res1999;29,36-40. [PubMed]
 
Kennedy, CR, Cogswell, JJ Late onset ornithine carbamoyl transferase deficiency in males.Arch Dis Child1989;64,638
 
Kay, JD, Hilton-Jones, D, Hyman, N Valproate toxicity and ornithine carbamoyltransferase deficiency.Lancet1986;2,1283-1284
 
Tripp, JH, Hargreaves, T, Anthony, PP, et al Sodium valproate and ornithine carbamyl transferase deficiency.Lancet1981;1,1165-1166
 
Oechsner, M, Steen, C, Sturenburg, HJ, et al Hyperammonaemic encephalopathy after initiation of valproate therapy in unrecognised ornithine transcarbamylase deficiency.J Neurol Neurosurg Psychiatry1998;64,680-682. [PubMed]
 
Schimanski, U, Krieger, D, Horn, M, et al A novel two-nucleotide deletion in the ornithine transcarbamylase gene causing fatal hyperammonia in early pregnancy.Hepatology1996;24,1413-1415. [PubMed]
 
Honeycutt, D, Callahan, K, Rutledge, L, et al Heterozygote ornithine transcarbamylase deficiency presenting as symptomatic hyperammonemia during initiation of valproate therapy.Neurology1992;42,666-668. [PubMed]
 
Raby, WN Carnitine for valproic acid-induced hyperammonemia.Am J Psychiatry1997;154,1168-1169. [PubMed]
 
Duarte, J, Macias, S, Coria, F, et al Valproate-induced coma: case report and literature review.Ann Pharmacother1993;27,582-583. [PubMed]
 
Batshaw, ML, Brusilow, SW Valproate-induced hyperammonemia.Ann Neurol1982;11,319-321. [PubMed]
 
Ambrosetto, G, Riva, R, Baruzzi, A Hyperammonemia in asterixis induced by carbamazepine: two case reports.Acta Neurol Scand1984;69,186-189. [PubMed]
 
Rivelli, M, el-Mallakh, RS, Nelson, WH Carbamazepine-associated asterixis and hyperammonemia.Am J Psychiatry1988;145,269-270
 
Bertrand, P, Faro, A, Cantwell, P, et al Intravenous ribavirin and hyperammonemia in an immunocompromised patient infected with adenovirus.Pharmacotherapy2000;20,1216-1220. [PubMed]
 
Sekas, G, Paul, HS Hyperammonemia and carnitine deficiency in a patient receiving sulfadiazine and pyrimethamine.Am J Med1993;95,112-113. [PubMed]
 
Miga, DE, Roth, KS Hyperammonemia: the silent killer.South Med J1993;86,742-747. [PubMed]
 
Batshaw, ML Hyperammonemia.Curr Probl Pediatr1984;14,1-69
 
Oizumi, J, Ng, WG, Koch, R, et al Partial ornithine transcarbamylase deficiency associated with recurrent hyperammonemia, lethargy and depressed sensorium.Clin Genet1984;25,538-542. [PubMed]
 
Finkelstein, JE, Hauser, ER, Leonard, CO, et al Late-onset ornithine transcarbamylase deficiency in male patients.J Pediatr1990;117,897-902. [PubMed]
 
Yudkoff, M, Yang, W, Snodgrass, PJ, et al Ornithine transcarbamylase deficiency in a boy with normal development.J Pediatr1980;96,441-443. [PubMed]
 
Drogari, E, Leonard, JV Late onset ornithine carbamoyl transferase deficiency in males.Arch Dis Child1988;63,1363-1367. [PubMed]
 
Batshaw, ML, Msall, M, Beaudet, AL, et al Risk of serious illness in heterozygotes for ornithine transcarbamylase deficiency.J Pediatr1986;108,236-241. [PubMed]
 
Hayasaka, K, Metoki, K, Ishiguro, S, et al Partial ornithine transcarbamylase deficiency in females: diagnosis by an immunohistochemical method.Eur J Pediatr1987;146,370-372. [PubMed]
 
Gilchrist, JM, Coleman, RA Ornithine transcarbamylase deficiency: adult onset of severe symptoms.Ann Intern Med1987;106,556-558. [PubMed]
 
Arn, PH, Hauser, ER, Thomas, GH, et al Hyperammonemia in women with a mutation at the ornithine carbamoyltransferase locus: a cause of postpartum coma.N Engl J Med1990;322,1652-1655. [PubMed]
 
Perpoint, T, Argaud, L, Blanc, Q, et al Fatal hyperammonemic coma caused by ornithine transcarbamylase deficiency in a woman.Intensive Care Med2001;27,1962. [PubMed]
 
Rimbaux, S, Hommet, C, Perrier, D, et al Adult onset ornithine transcarbamylase deficiency: an unusual cause of semantic disorders.J Neurol Neurosurg Psychiatry2004;75,1073-1075. [PubMed]
 
Legras, A, Labarthe, F, Maillot, F, et al Late diagnosis of ornithine transcarbamylase defect in three related female patients: polymorphic presentations.Crit Care Med2002;30,241-244. [PubMed]
 
Gyato, K, Wray, J, Huang, ZJ, et al Metabolic and neuropsychological phenotype in women heterozygous for ornithine transcarbamylase deficiency.Ann Neurol2004;55,80-86. [PubMed]
 
McReynolds, JW, Crowley, B, Mahoney, MJ, et al Autosomal recessive inheritance of human mitochondrial carbamyl phosphate synthetase deficiency.Am J Hum Genet1981;33,345-353. [PubMed]
 
Lo, WD, Sloan, HR, Sotos, JF, et al Late clinical presentation of partial carbamyl phosphate synthetase I deficiency.Am J Dis Child1993;147,267-269. [PubMed]
 
Verbiest, HB, Straver, JS, Colombo, JP, et al Carbamyl phosphate synthetase-1 deficiency discovered after valproic acid-induced coma.Acta Neurol Scand1992;86,275-279. [PubMed]
 
Wong, LJ, Craigen, WJ, O’Brien, WE Postpartum coma and death due to carbamoyl-phosphate synthetase I deficiency.Ann Intern Med1994;120,216-217. [PubMed]
 
Call, G, Seay, AR, Sherry, R, et al Clinical features of carbamyl phosphate synthetase-I deficiency in an adult.Ann Neurol1984;16,90-93. [PubMed]
 
Batshaw, M, Brusilow, S, Walser, M Treatment of carbamyl phosphate synthetase deficiency with keto analogues of essential amino acids.N Engl J Med1975;292,1085-1090. [PubMed]
 
Sassaman, EA, Zartler, AS, Mulick, JA Cognitive functioning in two sisters with carbamyl phosphate synthetase I deficiency.J Pediatr Psychol1981;6,171-175. [PubMed]
 
Segal, S, Roth, KS Inborn errors of metabolism: a new purview of internal medicine.Ann Intern Med1994;120,245-246. [PubMed]
 
Summar, ML Molecular genetic research into carbamoyl-phosphate synthase I: molecular defects and linkage markers.J Inherit Metab Dis1998;21,30-39. [PubMed]
 
Elpeleg, O, Shaag, A, Ben-Shalom, E, et al N-acetylglutamate synthase deficiency and the treatment of hyperammonemic encephalopathy.Ann Neurol2002;52,845-849. [PubMed]
 
Belanger-Quintana, A, Martinez-Pardo, M, Garcia, MJ, et al Hyperammonaemia as a cause of psychosis in an adolescent.Eur J Pediatr2003;162,773-775. [PubMed]
 
Caldovic, L, Morizono, H, Panglao, MG, et al Late onset N-acetylglutamate synthase deficiency caused by hypomorphic alleles.Hum Mutat2005;25,293-298. [PubMed]
 
Coude, FX, Sweetman, L, Nyhan, WL Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria: a possible explanation for hyperammonemia in propionic and methylmalonic acidemia.J Clin Invest1979;64,1544-1551. [PubMed]
 
Coude, FX, Rabier, D, Cathelineau, L, et al A mechanism for valproate-induced hyperammonemia.Adv Exp Med Biol1982;153,153-161. [PubMed]
 
Ishikawa, F, Nakamuta, M, Kato, M, et al Reversibility of serum NH3 level in a case of sudden onset and rapidly progressive case of type 2 citrullinemia.Intern Med2000;39,925-929. [PubMed]
 
Kobayashi, K, Shaheen, N, Kumashiro, R, et al A search for the primary abnormality in adult-onset type II citrullinemia.Am J Hum Genet1993;53,1024-1030. [PubMed]
 
Grisar, T Argininosuccinic aciduria in adult: a clinical, electrophysiological and biochemical study.Adv Exp Med Biol1982;153,83-93. [PubMed]
 
Oshiro, S, Kochinda, T, Tana, T, et al A patient with adult-onset type II citrullinemia on long-term hemodialysis: reversal of clinical symptoms and brain MRI findings.Am J Kidney Dis2002;39,189-192. [PubMed]
 
Maruyama, H, Ogawa, M, Nishio, T, et al Citrullinemia type II in a 64-year-old man with fluctuating serum citrulline levels: mutations in the SLC25A13 gene.J Neurol Sci2001;193,63. [PubMed]
 
Miyamoto, T, Kanazawa, N, Kato, S, et al Diagnosis of Japanese patients with HHH syndrome by molecular genetic analysis: a common mutation, R179X.J Hum Genet2001;46,260-262. [PubMed]
 
Salvi, S, Santorelli, FM, Bertini, E, et al Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.Neurology2001;57,911-914. [PubMed]
 
Tuchman, M, Knopman, DS, Shih, VE Episodic hyperammonemia in adult siblings with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome.Arch Neurol1990;47,1134-1137. [PubMed]
 
Korman, S, Kanazawa, M, Bassam, A, et al Hyperornithinemia, hyperammonemia and homocitrullinemia syndrome with evidence of mitochondrial dysfunction due to a novel SLC25A15 (ORNT1) gene mutation in a Palestinian family.J Neurol Sci2004;218,53-58. [PubMed]
 
Gare, M, Shalit, M, Gutman, A Lysinuric protein intolerance presenting as coma in a middle-aged man.West J Med1996;165,231-233. [PubMed]
 
Kato, T, Mizutani, N, Ban, M Hyperammonemia in lysinuric protein intolerance.Pediatrics1984;73,489-492. [PubMed]
 
Parto, K, Svedstrom, E, Majurin, ML, et al Pulmonary manifestations in lysinuric protein intolerance.Chest1993;104,1176-1182. [PubMed]
 
Shaw, PJ, Dale, G, Bates, D Familial lysinuric protein intolerance presenting as coma in two adult siblings.J Neurol Neurosurg Psychiatry1989;52,648-651. [PubMed]
 
Lemay, JF, Lambert, MA, Mitchell, GA, et al Hyperammonemia-hyperornithinemia-homocitrullinuria syndrome: neurologic, ophthalmologic, and neuropsychologic examination of six patients.J Pediatr1992;121,725-730. [PubMed]
 
Smith, L, Lambert, MA, Brochu, P, et al Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome: presentation as acute liver disease with coagulopathy.J Pediatr Gastroenterol Nutr1992;15,431-436. [PubMed]
 
DiRocco, M, Garibotto, G, Rossi, GA, et al Role of haematological, pulmonary and renal complications in the long-term prognosis of patients with lysinuric protein intolerance.Eur J Pediatr1993;152,437-440. [PubMed]
 
Davies, SM, Szabo, E, Wagner, JE, et al Idiopathic hyperammonemia: a frequently lethal complication of bone marrow transplantation.Bone Marrow Transplant1996;17,1119-1125. [PubMed]
 
Ho, AY, Mijovic, A, Pagliuca, A, et al Idiopathic hyperammonaemia syndrome following allogeneic peripheral blood progenitor cell transplantation (allo-PBPCT).Bone Marrow Transplant1997;20,1007-1008. [PubMed]
 
Liaw, CC, Liaw, SJ, Wang, CH, et al Transient hyperammonemia related to chemotherapy with continuous infusion of high-dose 5-fluorouracil.Anticancer Drugs1993;4,311-315. [PubMed]
 
Mitchell, RB, Wagner, JE, Karp, JE, et al Syndrome of idiopathic hyperammonemia after high-dose chemotherapy: review of nine cases.Am J Med1988;85,662-667. [PubMed]
 
Tse, N, Cederbaum, S, Glaspy, JA Hyperammonemia following allogeneic bone marrow transplantation.Am J Hematol1991;38,140-141. [PubMed]
 
Espinos, J, Rifon, J, Perez-Calvo, J, et al Idiopathic hyperammonemia following high-dose chemotherapy.Bone Marrow Transplant2006;37,899. [PubMed]
 
Lichtenstein, GR, Yang, YX, Nunes, FA, et al Fatal hyperammonemia after orthotopic lung transplantation.Ann Intern Med2000;132,283-287. [PubMed]
 
del Rosario, M, Werlin, SL, Lauer, SJ Hyperammonemic encephalopathy after chemotherapy: survival after treatment with sodium benzoate and sodium phenylacetate.J Clin Gastroenterol1997;25,682-684. [PubMed]
 
Brusilow, SW Hyperammonemic encephalopathy.Medicine (Baltimore)2002;81,240-249. [PubMed]
 
Wraith, JE Ornithine carbamoyltransferase deficiency.Arch Dis Child2001;84,84-88. [PubMed]
 
Steiner, RD, Cederbaum, SD Laboratory evaluation of urea cycle disorders.J Pediatr2001;138,S21-S29. [PubMed]
 
Scaglia, F, Zheng, Q, O’Brien, WE, et al An integrated approach to the diagnosis and prospective management of partial ornithine transcarbamylase deficiency.Pediatrics2002;109,150-152. [PubMed]
 
Burlina, AB, Ogier, H, Korall, H, et al Long-term treatment with sodium phenylbutyrate in ornithine transcarbamylase-deficient patients.Mol Genet Metab2001;72,351-355. [PubMed]
 
Msall, M, Batshaw, ML, Suss, R, et al Neurologic outcome in children with inborn errors of urea synthesis: outcome of urea-cycle enzymopathies.N Engl J Med1984;310,1500-1505. [PubMed]
 
Uchino, T, Endo, F, Matsuda, I Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan.J Inherit Metab Dis1998;21,151-159. [PubMed]
 
Plochl, W, Spiss, CK, Plochl, E Death after transplantation of a liver from a donor with unrecognized ornithine transcarbamylase deficiency.N Engl J Med1999;341,921-922
 
Plochl, W, Plochl, E, Pokorny, H, et al Multiorgan donation from a donor with unrecognized ornithine transcarbamylase deficiency.Transpl Int2001;14,196-201. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Organs responsible for ammonia metabolism.Grahic Jump Location
Figure Jump LinkFigure 4. Response to treatment. CVVHD = continuous venovenous hemodiafiltration; HD = hemodiafiltration.Grahic Jump Location
Figure Jump LinkFigure 5. Diagnostic algorithm for UCD. ASA = acetylsalicylic acid.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Evaluation and Treatment of Hyperammonemia*
* 

TURP = transurethral resection of the prostate; SIRS = systemic inflammatory response syndrome; EBV = Epstein-Barr virus; TB = tuberculosis; CMV = cytomegalovirus.

Table Graphic Jump Location
Table 2. Causes of Hyperammonemia in Adults*
* 

TIPSS = transjugular intrahepatic portosystemic shunt.

Table Graphic Jump Location
Table 3. Drugs Associated With Hyperammonemia*
* 

MDMA = 3,4 methylenedioxymethamphetamine.

References

Bachmann, C (2002) Mechanisms of hyperammonemia.Clin Chem Lab Med40,653-662. [PubMed] [CrossRef]
 
Vince, A, Dawson, AM, Park, N, et al Ammonia production by intestinal bacteria.Gut1973;14,171-177. [PubMed]
 
Karim, Z, Szutkowska, M, Vernimmen, C, et al Renal handling of NH3/NH4+: recent concepts.Nephron Physiol2005;101,77-81
 
Olde Damink, SW, Dejong, CH, Deutz, NE, et al Kidney plays a major role in ammonia homeostasis after portasystemic shunting in patients with cirrhosis.Am J Physiol Gastrointest Liver Physiol2006;291,G189-G194. [PubMed]
 
Olde Damink, SW, Dejong, CH, Deutz, NE, et al Upper gastrointestinal bleeding: an ammoniagenic and catabolic event due to the total absence of isoleucine in the haemoglobin molecule.Med Hypotheses1999;52,515-519. [PubMed]
 
Clemmesen, JO, Kondrup, J, Ott, P Splanchnic and leg exchange of amino acids and ammonia in acute liver failure.Gastroenterology2000;118,1131-1139. [PubMed]
 
Clemmesen, JO, Larsen, FS, Kondrup, J, et al Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration.Hepatology1999;29,648-653. [PubMed]
 
Lockwood, AH Blood ammonia levels and hepatic encephalopathy.Metab Brain Dis2004;19,345-349. [PubMed]
 
Ong, JP, Aggarwal, A, Krieger, D, et al Correlation between ammonia levels and the severity of hepatic encephalopathy.Am J Med2003;114,188-193. [PubMed]
 
Olde Damink, SW, Jalan, R, Duetz, N, et al The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis.Hepatology2003;37,1277-1285. [PubMed]
 
Butterworth, RF Effects of hyperammonaemia on brain function.J Inherit Metab Dis1998;21,6-20. [PubMed]
 
Vaquero, J, Chung, C, Cahill, ME, et al Pathogenesis of hepatic encephalopathy in acute liver failure.Semin Liver Dis2003;23,259-269. [PubMed]
 
Shawcross, D, Jalan, R The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.Cell Mol Life Sci2005;62,2295-2304. [PubMed]
 
Butterworth, RF Glutamate transporter and receptor function in disorders of ammonia metabolism.Ment Retard Dev Disabil Res Rev2001;7,276-279. [PubMed]
 
Ott, P, Clemmesen, O, Larsen, FS Cerebral metabolic disturbances in the brain during acute liver failure: from hyperammonemia to energy failure and proteolysis.Neurochem Int2005;47,13-18. [PubMed]
 
Strauss, GI, Knudsen, GM, Kondrup, J, et al Cerebral metabolism of ammonia and amino acids in patients with fulminant hepatic failure.Gastroenterology2001;121,1109-1119. [PubMed]
 
Tofteng, F, Hauerberg, J, Hansen, B, et al Persistent arterial hyperammonemia increases the concentration of glutamine and alanine in the brain and correlates with intracranial pressure in patients with fulminant hepatic failure.J Cereb Blood Flow Metab2006;26,21-27. [PubMed]
 
Jalan, R Intracranial hypertension in acute liver failure: pathophysiological basis of rational management.Semin Liver Dis2003;23,271-282. [PubMed]
 
Blei, AT, Olafsson, S, Webster, S, et al Complications of intracranial pressure monitoring in fulminant hepatic failure.Lancet1993;341,157-158. [PubMed]
 
Vaquero, J, Blei, AT Mild hypothermia for acute liver failure: a review of mechanisms of action.J Clin Gastroenterol2005;39,S147-S157. [PubMed]
 
Summar, M, Barr, F, Dawling, S, et al Unmasked adult-onset urea cycle disorders in the critical care setting.Crit Care Clin2005;21(suppl),S1-S8
 
Canalese, J, Gimson, A, Davis, C Controlled trial of dexamethasone and mannitol for cerebral oedema of fulminant hepatic failure.Gut1982;23,625-629. [PubMed]
 
Clemmesen, J, Hansen, B, Larsen, FS Indomethacin normalizes intracranial pressure in acute liver failure: a twenty-three year old woman treated with indomethacin.Hepatology1997;26,1423-1425. [PubMed]
 
Wijdicks, EF, Nyberg, SL Propofol to control intracranial pressure in fulminant hepatic failure.Transplant Proc2002;34,1220-1222. [PubMed]
 
Ellis, A, Wendon, J, Williams, R Subclinical seizure activity and prophylactic phenytoin infusion in acute liver failure: a controlled clinical trial.Hepatology2000;38,536-541
 
Watanabe, A, Sakai, T, Sato, S, et al Clinical efficacy of lactulose in cirrhotic patients with and without subclinical hepatic encephalopathy.Hepatology1997;26,1410-1414. [PubMed]
 
Rolando, N, Gimson, A, Wade, J, et al Prospective controlled trial of selective parenteral and enteral antimicrobial regimen in fulminant liver failure.Hepatology1993;17,196-201. [PubMed]
 
Rolando, N, Harvey, F, Brahm, J, et al Fungal infection: a common, unrecognised complication of acute liver failure.J Hepatol1991;12,1-9. [PubMed]
 
Chang, MY, Fang, JT, Chen, YC, et al Continuous venovenous haemofiltration in hyperammonaemic coma of an adult with non-diagnosed partial ornithine transcarbamylase deficiency.Nephrol Dial Transplant1999;14,1282-1284. [PubMed]
 
Donn, SM, Swartz, RD, Thoene, JG Comparison of exchange transfusion, peritoneal dialysis, and hemodialysis for the treatment of hyperammonemia in an anuric newborn infant.J Pediatr1979;95,67-70. [PubMed]
 
Treem, WR Inherited and acquired syndromes of hyperammonemia and encephalopathy in children.Semin Liver Dis1994;14,236-258. [PubMed]
 
Rutledge, SL, Havens, PL, Haymond, MW, et al Neonatal hemodialysis: effective therapy for the encephalopathy of inborn errors of metabolism.J Pediatr1990;116,125-128. [PubMed]
 
Falk, MC, Knight, JF, Roy, LP, et al Continuous venovenous haemofiltration in the acute treatment of inborn errors of metabolism.Pediatr Nephrol1994;8,330-333. [PubMed]
 
Mathias, RS, Kostiner, D, Packman, S Hyperammonemia in urea cycle disorders: role of the nephrologist.Am J Kidney Dis2001;37,1069-1080. [PubMed]
 
Summar, M, Pietsch, J, Deshpande, J, et al Effective hemodialysis and hemofiltration driven by an extracorporeal membrane oxygenation pump in infants with hyperammonemia.J Pediatr1996;128,379-382. [PubMed]
 
Wong, KY, Wong, SN, Lam, SY, et al Ammonia clearance by peritoneal dialysis and continuous arteriovenous hemodiafiltration.Pediatr Nephrol1998;12,589-591. [PubMed]
 
Brusilow, S, Horwich, A Urea cycle enzymes. 8th ed.2001 McGraw-Hill. New York, NY:
 
Mizutani, N, Maehara, M, Hayakawa, C, et al Hyperargininemia: clinical course and treatment with sodium benzoate and phenylacetic acid.Brain Dev1983;5,555-563. [PubMed]
 
Batshaw, ML, MacArthur, RB, Tuchman, M Alternative pathway therapy for urea cycle disorders: twenty years later.J Pediatr2001;138,S46-S54. [PubMed]
 
Brusilow, SW, Danney, M, Waber, LJ, et al Treatment of episodic hyperammonemia in children with inborn errors of urea synthesis.N Engl J Med1984;310,1630-1634. [PubMed]
 
Brusilow, SW Arginine, an indispensable amino acid for patients with inborn errors of urea synthesis.J Clin Invest1984;74,2144-2148. [PubMed]
 
Malaguarnera, M, Pistone, G, Astuto, M, et al L-Carnitine in the treatment of mild or moderate hepatic encephalopathy.Dig Dis2003;21,271-275. [PubMed]
 
Rahman, T, Hodgson, H Clinical management of acute hepatic failure.Intensive Care Med2001;27,467-476. [PubMed]
 
Sass, DA, Shakil, AO Fulminant hepatic failure.Liver Transpl2005;11,594-605. [PubMed]
 
Jan, D, Laurent, J, Lacaille, F, et al Liver transplantation in children with inherited metabolic disorders.Transplant Proc1995;27,1706-1707. [PubMed]
 
Ikeda, S, Yazaki, M, Takei, Y, et al Type II (adult onset) citrullinaemia: clinical pictures and the therapeutic effect of liver transplantation.J Neurol Neurosurg Psychiatry2001;71,663-670. [PubMed]
 
Yazaki, M, Ikeda, S, Takei, Y, et al Complete neurological recovery of an adult patient with type II citrullinemia after living related partial liver transplantation.Transplantation1996;62,1679-1684. [PubMed]
 
Todo, S, Starzl, TE, Tzakis, A, et al Orthotopic liver transplantation for urea cycle enzyme deficiency.Hepatology1992;15,419-422. [PubMed]
 
Largilliere, C, Houssin, D, Gottrand, F, et al Liver transplantation for ornithine transcarbamylase deficiency in a girl.J Pediatr1989;115,415-417. [PubMed]
 
Felig, DM, Brusilow, SW, Boyer, JL Hyperammonemic coma due to parenteral nutrition in a woman with heterozygous ornithine transcarbamylase deficiency.Gastroenterology1995;109,282-284. [PubMed]
 
Benque, A, Bommelaer, G, Rosental, G Chronic vomiting in a case of citrullinaemia detected after treatment by total parenteral nutrition.Gut1984;25,531-533. [PubMed]
 
Trivedi, M, Zafar, S, Spalding, MJ, et al Ornithine transcarbamylase deficiency unmasked because of gastrointestinal bleeding.J Clin Gastroenterol2001;32,340-343. [PubMed]
 
Cheang, HK, Rangecroft, L, Plant, ND, et al Hyperammonaemia due to Klebsiella infection in a neuropathic bladder.Pediatr Nephrol1998;12,658-659. [PubMed]
 
Kaveggia, FF, Thompson, JS, Schafer, EC, et al Hyperammonemic encephalopathy in urinary diversion with urea-splitting urinary tract infection.Arch Intern Med1990;150,2389-2392. [PubMed]
 
Laube, GF, Superti-Furga, A, Losa, M, et al Hyperammonaemic encephalopathy in a 13-year-old boy.Eur J Pediatr2002;161,163-164. [PubMed]
 
Zuberi, SM, Stephenson, JB, Azmy, AF, et al Hyperammonaemic encephalopathy after a subureteric injection for vesicoureteric reflux.Arch Dis Child1998;79,363-364. [PubMed]
 
Samtoy, B, DeBeukelaer, MM Ammonia encephalopathy secondary to urinary tract infection withProteus mirabilis.Pediatrics1980;65,294-297. [PubMed]
 
Barnes, PM, Wheldon, DB, Eggerding, C, et al Hyperammonaemia and disseminated herpes simplex infection in the neonatal period.Lancet1982;1,1362-1363
 
Hawkes, ND, Thomas, GA, Jurewicz, A, et al Non-hepatic hyperammonaemia: an important, potentially reversible cause of encephalopathy.Postgrad Med J2001;77,717-722. [PubMed]
 
Cascino, GD, Jensen, JM, Nelson, LA, et al Periodic hyperammonemic encephalopathy associated with a ureterosigmoidostomy.Mayo Clin Proc1989;64,653-656. [PubMed]
 
Gilbert, GJ Acute ammonia intoxication 37 years after ureterosigmoidostomy.South Med J1988;81,1443-1445. [PubMed]
 
Matsuzaki, H, Uchiba, M, Yoshimura, K, et al Hyperammonemia in multiple myeloma.Acta Haematol1990;84,130-134. [PubMed]
 
Fine, P, Adler, K, Gerstenfeld, D Idiopathic hyperammonemia after high-dose chemotherapy.Am J Med1989;86,629
 
Perez Retortillo, JA, Marco, F, Amutio, E, et al Hyperammonemic encephalopathy in multiple myeloma.Haematologica1998;83,956-957. [PubMed]
 
Kwan, L, Wang, C, Levitt, L Hyperammonemic encephalopathy in multiple myeloma.N Engl J Med2002;346,1674-1675
 
Takimoto, Y, Imanaka, F, Hayashi, Y, et al A patient with ammonia-producing multiple myeloma showing hyperammonemic encephalopathy.Leukemia1996;10,918-919. [PubMed]
 
Keller, DR, Keller, K Hyperammonemic encephalopathy in multiple myeloma.Am J Hematol1998;57,264-265. [PubMed]
 
Ostapowicz, G, Fontana, RJ, Schiodt, FV, et al Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States.Ann Intern Med2002;137,947-954. [PubMed]
 
Ryder, KW, Olson, JF, Kahnoski, RJ, et al Hyperammonemia after transurethral resection of the prostate: a report of 2 cases.J Urol1984;132,995-997. [PubMed]
 
DeLong, GR, Glick, TH Ammonia metabolism in Reye syndrome and the effect of citrulline.Ann Neurol1982;11,53-58. [PubMed]
 
Makela, AL, Lang, H, Korpela, P Toxic encephalopathy with hyperammonaemia during high-dose salicylate therapy.Acta Neurol Scand1980;61,146-156. [PubMed]
 
Kulick, SK, Kramer, DA Hyperammonemia secondary to valproic acid as a cause of lethargy in a postictal patient.Ann Emerg Med1993;22,610-612. [PubMed]
 
Verrotti, A, Greco, R, Morgese, G, et al Carnitine deficiency and hyperammonemia in children receiving valproic acid with and without other anticonvulsant drugs.Int J Clin Lab Res1999;29,36-40. [PubMed]
 
Kennedy, CR, Cogswell, JJ Late onset ornithine carbamoyl transferase deficiency in males.Arch Dis Child1989;64,638
 
Kay, JD, Hilton-Jones, D, Hyman, N Valproate toxicity and ornithine carbamoyltransferase deficiency.Lancet1986;2,1283-1284
 
Tripp, JH, Hargreaves, T, Anthony, PP, et al Sodium valproate and ornithine carbamyl transferase deficiency.Lancet1981;1,1165-1166
 
Oechsner, M, Steen, C, Sturenburg, HJ, et al Hyperammonaemic encephalopathy after initiation of valproate therapy in unrecognised ornithine transcarbamylase deficiency.J Neurol Neurosurg Psychiatry1998;64,680-682. [PubMed]
 
Schimanski, U, Krieger, D, Horn, M, et al A novel two-nucleotide deletion in the ornithine transcarbamylase gene causing fatal hyperammonia in early pregnancy.Hepatology1996;24,1413-1415. [PubMed]
 
Honeycutt, D, Callahan, K, Rutledge, L, et al Heterozygote ornithine transcarbamylase deficiency presenting as symptomatic hyperammonemia during initiation of valproate therapy.Neurology1992;42,666-668. [PubMed]
 
Raby, WN Carnitine for valproic acid-induced hyperammonemia.Am J Psychiatry1997;154,1168-1169. [PubMed]
 
Duarte, J, Macias, S, Coria, F, et al Valproate-induced coma: case report and literature review.Ann Pharmacother1993;27,582-583. [PubMed]
 
Batshaw, ML, Brusilow, SW Valproate-induced hyperammonemia.Ann Neurol1982;11,319-321. [PubMed]
 
Ambrosetto, G, Riva, R, Baruzzi, A Hyperammonemia in asterixis induced by carbamazepine: two case reports.Acta Neurol Scand1984;69,186-189. [PubMed]
 
Rivelli, M, el-Mallakh, RS, Nelson, WH Carbamazepine-associated asterixis and hyperammonemia.Am J Psychiatry1988;145,269-270
 
Bertrand, P, Faro, A, Cantwell, P, et al Intravenous ribavirin and hyperammonemia in an immunocompromised patient infected with adenovirus.Pharmacotherapy2000;20,1216-1220. [PubMed]
 
Sekas, G, Paul, HS Hyperammonemia and carnitine deficiency in a patient receiving sulfadiazine and pyrimethamine.Am J Med1993;95,112-113. [PubMed]
 
Miga, DE, Roth, KS Hyperammonemia: the silent killer.South Med J1993;86,742-747. [PubMed]
 
Batshaw, ML Hyperammonemia.Curr Probl Pediatr1984;14,1-69
 
Oizumi, J, Ng, WG, Koch, R, et al Partial ornithine transcarbamylase deficiency associated with recurrent hyperammonemia, lethargy and depressed sensorium.Clin Genet1984;25,538-542. [PubMed]
 
Finkelstein, JE, Hauser, ER, Leonard, CO, et al Late-onset ornithine transcarbamylase deficiency in male patients.J Pediatr1990;117,897-902. [PubMed]
 
Yudkoff, M, Yang, W, Snodgrass, PJ, et al Ornithine transcarbamylase deficiency in a boy with normal development.J Pediatr1980;96,441-443. [PubMed]
 
Drogari, E, Leonard, JV Late onset ornithine carbamoyl transferase deficiency in males.Arch Dis Child1988;63,1363-1367. [PubMed]
 
Batshaw, ML, Msall, M, Beaudet, AL, et al Risk of serious illness in heterozygotes for ornithine transcarbamylase deficiency.J Pediatr1986;108,236-241. [PubMed]
 
Hayasaka, K, Metoki, K, Ishiguro, S, et al Partial ornithine transcarbamylase deficiency in females: diagnosis by an immunohistochemical method.Eur J Pediatr1987;146,370-372. [PubMed]
 
Gilchrist, JM, Coleman, RA Ornithine transcarbamylase deficiency: adult onset of severe symptoms.Ann Intern Med1987;106,556-558. [PubMed]
 
Arn, PH, Hauser, ER, Thomas, GH, et al Hyperammonemia in women with a mutation at the ornithine carbamoyltransferase locus: a cause of postpartum coma.N Engl J Med1990;322,1652-1655. [PubMed]
 
Perpoint, T, Argaud, L, Blanc, Q, et al Fatal hyperammonemic coma caused by ornithine transcarbamylase deficiency in a woman.Intensive Care Med2001;27,1962. [PubMed]
 
Rimbaux, S, Hommet, C, Perrier, D, et al Adult onset ornithine transcarbamylase deficiency: an unusual cause of semantic disorders.J Neurol Neurosurg Psychiatry2004;75,1073-1075. [PubMed]
 
Legras, A, Labarthe, F, Maillot, F, et al Late diagnosis of ornithine transcarbamylase defect in three related female patients: polymorphic presentations.Crit Care Med2002;30,241-244. [PubMed]
 
Gyato, K, Wray, J, Huang, ZJ, et al Metabolic and neuropsychological phenotype in women heterozygous for ornithine transcarbamylase deficiency.Ann Neurol2004;55,80-86. [PubMed]
 
McReynolds, JW, Crowley, B, Mahoney, MJ, et al Autosomal recessive inheritance of human mitochondrial carbamyl phosphate synthetase deficiency.Am J Hum Genet1981;33,345-353. [PubMed]
 
Lo, WD, Sloan, HR, Sotos, JF, et al Late clinical presentation of partial carbamyl phosphate synthetase I deficiency.Am J Dis Child1993;147,267-269. [PubMed]
 
Verbiest, HB, Straver, JS, Colombo, JP, et al Carbamyl phosphate synthetase-1 deficiency discovered after valproic acid-induced coma.Acta Neurol Scand1992;86,275-279. [PubMed]
 
Wong, LJ, Craigen, WJ, O’Brien, WE Postpartum coma and death due to carbamoyl-phosphate synthetase I deficiency.Ann Intern Med1994;120,216-217. [PubMed]
 
Call, G, Seay, AR, Sherry, R, et al Clinical features of carbamyl phosphate synthetase-I deficiency in an adult.Ann Neurol1984;16,90-93. [PubMed]
 
Batshaw, M, Brusilow, S, Walser, M Treatment of carbamyl phosphate synthetase deficiency with keto analogues of essential amino acids.N Engl J Med1975;292,1085-1090. [PubMed]
 
Sassaman, EA, Zartler, AS, Mulick, JA Cognitive functioning in two sisters with carbamyl phosphate synthetase I deficiency.J Pediatr Psychol1981;6,171-175. [PubMed]
 
Segal, S, Roth, KS Inborn errors of metabolism: a new purview of internal medicine.Ann Intern Med1994;120,245-246. [PubMed]
 
Summar, ML Molecular genetic research into carbamoyl-phosphate synthase I: molecular defects and linkage markers.J Inherit Metab Dis1998;21,30-39. [PubMed]
 
Elpeleg, O, Shaag, A, Ben-Shalom, E, et al N-acetylglutamate synthase deficiency and the treatment of hyperammonemic encephalopathy.Ann Neurol2002;52,845-849. [PubMed]
 
Belanger-Quintana, A, Martinez-Pardo, M, Garcia, MJ, et al Hyperammonaemia as a cause of psychosis in an adolescent.Eur J Pediatr2003;162,773-775. [PubMed]
 
Caldovic, L, Morizono, H, Panglao, MG, et al Late onset N-acetylglutamate synthase deficiency caused by hypomorphic alleles.Hum Mutat2005;25,293-298. [PubMed]
 
Coude, FX, Sweetman, L, Nyhan, WL Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria: a possible explanation for hyperammonemia in propionic and methylmalonic acidemia.J Clin Invest1979;64,1544-1551. [PubMed]
 
Coude, FX, Rabier, D, Cathelineau, L, et al A mechanism for valproate-induced hyperammonemia.Adv Exp Med Biol1982;153,153-161. [PubMed]
 
Ishikawa, F, Nakamuta, M, Kato, M, et al Reversibility of serum NH3 level in a case of sudden onset and rapidly progressive case of type 2 citrullinemia.Intern Med2000;39,925-929. [PubMed]
 
Kobayashi, K, Shaheen, N, Kumashiro, R, et al A search for the primary abnormality in adult-onset type II citrullinemia.Am J Hum Genet1993;53,1024-1030. [PubMed]
 
Grisar, T Argininosuccinic aciduria in adult: a clinical, electrophysiological and biochemical study.Adv Exp Med Biol1982;153,83-93. [PubMed]
 
Oshiro, S, Kochinda, T, Tana, T, et al A patient with adult-onset type II citrullinemia on long-term hemodialysis: reversal of clinical symptoms and brain MRI findings.Am J Kidney Dis2002;39,189-192. [PubMed]
 
Maruyama, H, Ogawa, M, Nishio, T, et al Citrullinemia type II in a 64-year-old man with fluctuating serum citrulline levels: mutations in the SLC25A13 gene.J Neurol Sci2001;193,63. [PubMed]
 
Miyamoto, T, Kanazawa, N, Kato, S, et al Diagnosis of Japanese patients with HHH syndrome by molecular genetic analysis: a common mutation, R179X.J Hum Genet2001;46,260-262. [PubMed]
 
Salvi, S, Santorelli, FM, Bertini, E, et al Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.Neurology2001;57,911-914. [PubMed]
 
Tuchman, M, Knopman, DS, Shih, VE Episodic hyperammonemia in adult siblings with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome.Arch Neurol1990;47,1134-1137. [PubMed]
 
Korman, S, Kanazawa, M, Bassam, A, et al Hyperornithinemia, hyperammonemia and homocitrullinemia syndrome with evidence of mitochondrial dysfunction due to a novel SLC25A15 (ORNT1) gene mutation in a Palestinian family.J Neurol Sci2004;218,53-58. [PubMed]
 
Gare, M, Shalit, M, Gutman, A Lysinuric protein intolerance presenting as coma in a middle-aged man.West J Med1996;165,231-233. [PubMed]
 
Kato, T, Mizutani, N, Ban, M Hyperammonemia in lysinuric protein intolerance.Pediatrics1984;73,489-492. [PubMed]
 
Parto, K, Svedstrom, E, Majurin, ML, et al Pulmonary manifestations in lysinuric protein intolerance.Chest1993;104,1176-1182. [PubMed]
 
Shaw, PJ, Dale, G, Bates, D Familial lysinuric protein intolerance presenting as coma in two adult siblings.J Neurol Neurosurg Psychiatry1989;52,648-651. [PubMed]
 
Lemay, JF, Lambert, MA, Mitchell, GA, et al Hyperammonemia-hyperornithinemia-homocitrullinuria syndrome: neurologic, ophthalmologic, and neuropsychologic examination of six patients.J Pediatr1992;121,725-730. [PubMed]
 
Smith, L, Lambert, MA, Brochu, P, et al Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome: presentation as acute liver disease with coagulopathy.J Pediatr Gastroenterol Nutr1992;15,431-436. [PubMed]
 
DiRocco, M, Garibotto, G, Rossi, GA, et al Role of haematological, pulmonary and renal complications in the long-term prognosis of patients with lysinuric protein intolerance.Eur J Pediatr1993;152,437-440. [PubMed]
 
Davies, SM, Szabo, E, Wagner, JE, et al Idiopathic hyperammonemia: a frequently lethal complication of bone marrow transplantation.Bone Marrow Transplant1996;17,1119-1125. [PubMed]
 
Ho, AY, Mijovic, A, Pagliuca, A, et al Idiopathic hyperammonaemia syndrome following allogeneic peripheral blood progenitor cell transplantation (allo-PBPCT).Bone Marrow Transplant1997;20,1007-1008. [PubMed]
 
Liaw, CC, Liaw, SJ, Wang, CH, et al Transient hyperammonemia related to chemotherapy with continuous infusion of high-dose 5-fluorouracil.Anticancer Drugs1993;4,311-315. [PubMed]
 
Mitchell, RB, Wagner, JE, Karp, JE, et al Syndrome of idiopathic hyperammonemia after high-dose chemotherapy: review of nine cases.Am J Med1988;85,662-667. [PubMed]
 
Tse, N, Cederbaum, S, Glaspy, JA Hyperammonemia following allogeneic bone marrow transplantation.Am J Hematol1991;38,140-141. [PubMed]
 
Espinos, J, Rifon, J, Perez-Calvo, J, et al Idiopathic hyperammonemia following high-dose chemotherapy.Bone Marrow Transplant2006;37,899. [PubMed]
 
Lichtenstein, GR, Yang, YX, Nunes, FA, et al Fatal hyperammonemia after orthotopic lung transplantation.Ann Intern Med2000;132,283-287. [PubMed]
 
del Rosario, M, Werlin, SL, Lauer, SJ Hyperammonemic encephalopathy after chemotherapy: survival after treatment with sodium benzoate and sodium phenylacetate.J Clin Gastroenterol1997;25,682-684. [PubMed]
 
Brusilow, SW Hyperammonemic encephalopathy.Medicine (Baltimore)2002;81,240-249. [PubMed]
 
Wraith, JE Ornithine carbamoyltransferase deficiency.Arch Dis Child2001;84,84-88. [PubMed]
 
Steiner, RD, Cederbaum, SD Laboratory evaluation of urea cycle disorders.J Pediatr2001;138,S21-S29. [PubMed]
 
Scaglia, F, Zheng, Q, O’Brien, WE, et al An integrated approach to the diagnosis and prospective management of partial ornithine transcarbamylase deficiency.Pediatrics2002;109,150-152. [PubMed]
 
Burlina, AB, Ogier, H, Korall, H, et al Long-term treatment with sodium phenylbutyrate in ornithine transcarbamylase-deficient patients.Mol Genet Metab2001;72,351-355. [PubMed]
 
Msall, M, Batshaw, ML, Suss, R, et al Neurologic outcome in children with inborn errors of urea synthesis: outcome of urea-cycle enzymopathies.N Engl J Med1984;310,1500-1505. [PubMed]
 
Uchino, T, Endo, F, Matsuda, I Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan.J Inherit Metab Dis1998;21,151-159. [PubMed]
 
Plochl, W, Spiss, CK, Plochl, E Death after transplantation of a liver from a donor with unrecognized ornithine transcarbamylase deficiency.N Engl J Med1999;341,921-922
 
Plochl, W, Plochl, E, Pokorny, H, et al Multiorgan donation from a donor with unrecognized ornithine transcarbamylase deficiency.Transpl Int2001;14,196-201. [PubMed]
 
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