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Hyperammonemia and Liver

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Hyperammonemia
Ammonia is a normal constituent of all body fluids. At physiologic pH, it exists mainly as ammonium ion. Reference serum levels are less than 35 µmol/L. Excess ammonia is excreted as urea, which is synthesized in the liver through the urea cycle. Sources of ammonia include bacterial hydrolysis of urea and other nitrogenous compounds in the intestine, the purine-nucleotide cycle and amino acid transamination in skeletal muscle, and other metabolic processes in the kidneys and liver.
Increased entry of ammonia to the brain is a primary cause of neurological disorders associated with hyperammonemia, such as congenital deficiencies of urea cycle enzymes, hepatic encephalopathies, Reye syndrome, several other metabolic disorders, and some toxic encephalopathies.
Ammonia is a productof the metabolismof proteinsand other compounds,and itis required for the synthesis of essential cellular compounds. However,a 5- to 10-fold increase in ammonia in the blood induces toxic effects in mostanimal species, withalterations in the functionof the central nervous system.
Bothacuteand chronic hyperammonemia result inalterationsof the neurotransmitter system.
Based onanimal study findings, the mechanismofammonia neurotoxicityat the molecular level has been proposed.Acuteammonia intoxication inananimal model leads to increased extracellular concentrationof glutamate in the brainand results inactivationof the N-methyl D-aspartate (NMDA) receptor.Activationof this receptor mediatesATP depletionandammonia toxicity; sustained blockingof the NMDA receptor by continuousadministrationofantagonists dizocilpine (MK-801) or memantine prevents both phenomena, leading to significantly increased survival time in rats.[1] TheATP depletionis due toactivationof Na+/K+-ATPase, which, in turn,is a consequenceof decreased phosphorylation by protein kinase C.Activationof the NMDA receptoris probably the causeof seizures inacute hyperammonemia.
Neuropathologic evaluation demonstratesalteration in theastrocyte morphology. Recent studies demonstrateda significant downregulationof the gap–junction channel connexin 43, the water channelaquaporin 4 genes,and theastrocytic inward-rectifying potassium channel genes, colocalized toastrocytic end-feetat the brain vasculature, where they regulate potassiumand water transport.A downregulationof these channels in hyperammonemic mice suggestsanalteration inastrocyte-mediated waterand potassium homeostasis in the brainasa potential key factor in the developmentof brain edema.[2]
Also, studies on culturedastrocytes examined the potential roleof p53,a tumor suppressor proteinanda transcriptional factor, inammonia-induced neurotoxicity.Activationof p53 contributes toastrocyte swellingand glutamate uptake inhibition, leading to brain edema. Both processesare blocked by p53 inhibition.[3]
High levelsofammonia induce other metabolic changes thatare not mediated byactivationof the NMDA receptorand thusare not involved directly inammonia-inducedATP depletion or neurotoxicity. These include increases in brain levelsof lactate, pyruvate, glutamine,and free glucose,and decreases in brain levelsof glycogen, ketone bodies,and glutamate.
Chronic hyperammonemiais associated withan increase in inhibitory neurotransmissionasa consequenceof 2 factors. The firstis downregulationof glutamate receptors secondary to excessive extrasynapticaccumulationof glutamate. Inaddition, changes in the glutamate-nitric oxide-cGMP pathway result in impairmentof signal transductionassociated with NMDA receptors, leading toalteration in cognitionand learning.[4] The secondis an increased GABAergic tone resulting from benzodiazepine receptor overstimulation by endogenous benzodiazepinesand neurosteroids. These changes probably contribute to deteriorationof intellectual function, decreased consciousness,and coma. Treatmentof chronic hyperammonemic rats with inhibitorsof phosphodiesterase 5 restores the functionof glutamate-nitric oxide-cGMP pathwayand cGMP levels in rats’ brain, with restoredability to learna conditional task.[5]
RNA oxidationoffersan explanation for multiple disturbancesof neurotransmitter system, gene expression,and secondary cognitive deficiencies noticed in hepatic encephalopathy. In chronic hepatic encephalopathies,a small-gradeastrocyte swelling was observed without overt brain edema.Astrocyte edema produces reactive oxygenand nitrogen oxide species, resulting in RNA oxidationand increasedof free intracellular zinc. RNA oxidation may impair synthesis of postsynaptic proteins involved in learningand memory consolidation.[6]
Ammonia also increases the transportofaromaticaminoacids (eg, tryptophan)across the blood-brain barrier. This leads toan increase in the levelof serotonin, whichis the basis foranorexia in hyperammonemia.

Epidemiology
Frequency
United States
Collectingaccurate data onthe frequencyof metabolic disordersis difficult, becausethe information collectedis representativeof the particulararea orthe population group; however,the prevalenceof urea cycle disordersis estimatedat 1 case per 30,000 live births.
International
Ina recently published study,the incidenceof urea cycle disorders in British Columbia was shown to be 1 case per 53,717 persons, whichis approximately 1.9 cases per 100,000 live births.
Mortality/Morbidity
Coma and cerebral edema arethe major causesof death;the survivorsof coma havea high incidenceof intellectual impairment.
Race: These disorders have been observed inall races.
Sex: Allthe urea cycle disordersare inherited inanautosomal recessive pattern, except ornithine transcarbamoylase (OTC) deficiency, whichis inheritedasan X-linked trait; however, female carriersof the OTC gene can become symptomatic.
Age: Early-onset hyperammonemia presents inthe neonatal period. Urea cycle disorders can present later in life (see History).
History: Family history may reveal unexplained neonatal deaths or undiagnosed chronic illness. A history of males being affected is suggestive of OTC deficiency, which is inherited as an X-linked trait. Consanguinity results in an increased risk of inheriting a metabolic disorder. * Early-onset hyperammonemia presents in the neonatal period. The baby is usually well for the first day or two. As the ammonia level rises, the baby becomes symptomatic. The family gives a history of lethargy, irritability, poor feeding, and vomiting. These symptoms correlate with an ammonia level of 100-150 µmol/L, which is 2-3 times the reference range. This may be followed by hyperventilation and grunting respiration; seizures also may develop. * Late-onset hyperammonemia typically is due to urea cycle disorders, which can present later in life. The frequently altered clinical presentation of urea cycle disorders later in life develops from intrinsic differences in physiology based on age, as well as molecular aspects of the underlying biochemistry. Older children have greater energy reserves than neonates, allowing them to compensate for periods of stress. They also have a greater capacity and more opportunity to regulate their own environment. Adults with partial enzyme deficiency can become symptomatic when hyperammonemia is triggered by a stressful medical condition such as postpartum stress, heart-lung transplant, short bowel and kidney disease, parenteral nutrition with high nitrogen intake, and gastrointestinal bleeding. * Intermittent ataxia: Patients have an unstable gait and dysmetria. The intermittent nature of the symptoms is due to a periodic exacerbation of ammonia level. * Intellectual impairment: Episodic minor hyperammonemia may produce subtle intellectual deficits even in clinically asymptomatic individuals. * Failure to thrive: Children with an underlying metabolic disorder have suboptimal growth secondary to poor feeding and frequent vomiting. * Gait abnormality: In arginase deficiency, patients present with spastic diplegia, which manifests as toe walking. * Behavior disturbances: These include sleep disturbances, irritability, hyperactivity, manic episodes, and psychosis. * Epilepsy: Intractable seizures in a few patients have been secondary to an underlying urea cycle defect. * Recurrent Reye syndrome: A recurrent Reye syndromelike picture strongly suggests the possibility of a metabolic disorder. * Episodic headaches and cyclic vomiting may, rarely, be found to be caused by urea cycle defects. * Protein avoidance: Females with OTC deficiency may give a history of protein avoidance.
Physical
No specific physical findings are associated with hyperammonemia. Affected infants usually present with the following: * Dehydration secondary to vomiting * Lethargy * Tachypnea due to stimulation of the medullary center of respiration by the ammonium ion * Hypotonia as a nonspecific response to acute stress * Bulging fontanelle as a sign of raised intracranial pressure
Sometimes examinationreveals a peculiar finding, such as odor of "sweaty feet" in isovaleric acidemia or abnormally fragile hair in argininosuccinic aciduria. Infants with argininosuccinic lyase deficiencymay present with hepatomegaly.
Causes
Enzyme defects in urea cycle * N -acetylglutamate synthetase (NAGS) deficiency: Deficiency of this enzyme results in a lack of N -acetylglutamate, which is an activator of carbamoyl phosphate synthetase. Mode of inheritance is autosomal recessive. N -acetylglutamate also could become deficient if acetyl-CoA is not available. * Carbamoyl phosphate synthetase I (CPS I) deficiency: This defect is inherited in an autosomal recessive pattern. In the presence of N -acetylglutamate, ammonium ions combine with bicarbonate to form carbamoyl phosphate. The reaction takes place in hepatic mitochondria. Hyperammonemia develops as early as the first day of life. A majority of affected infants die in the neonatal period. This enzyme has been mapped to the short arm of chromosome 2. * Ornithine transcarbamoylase (OTC) deficiency: OTC also is found inside the mitochondria. In its presence, ornithine combines with carbamoyl phosphate to form citrulline, which is then transported out of the mitochondria. In the absence of the enzyme, accumulated carbamoyl phosphate enters the cytosol and participates in pyrimidine synthesis in the presence of CPS II. This is the most common urea cycle defect, with an estimated incidence of 1 case in 14,000 persons. It is transmitted as an X-linked trait. Neonatal onset is seen in males who have null mutations and thusno residual enzyme activity. Males who have significant residual enzyme activity and females whoare heterozygous for OTC deficiency present later with quite variable clinical pictures. Thus, as many as 60% of OTC deficiency diagnosesare made innon-neonates. The oldest reported patient was aged 61 years. * Argininosuccinic acid synthetase (AS) deficiency: Citrulline combines with aspartate to form argininosuccinic acid. The AS deficiency results in citrullinemia. Onset is usually between hours 24 and 72 of life, but late-onset forms have been described in the literature. The mode of inheritance is autosomal recessive. The gene for this defect has been localized to chromosome 9. * Argininosuccinic lyase (AL) deficiency: This enzyme cleaves argininosuccinic acid to yield fumarate and arginine. The lack of this enzyme leads to argininosuccinic aciduria. It is the second most common urea cycle disorder. Symptomsmay appear in the neonatal period or later in life. It also is inherited in an autosomal recessive pattern. Abnormally fragile hair (trichorrhexisnodosa) has been observed in these infants as early as age 2 weeks. The gene has been localized to chromosome 7. * Arginase deficiency: This enzyme is involved in the final step of the urea cycle when arginine is cleaved to form urea and ornithine. Its deficiency results in argininemia, which is the least frequent of the urea cycle disorders. Hyperammonemia isnot severe and the probable cause of neurotoxicity is arginine. The gene for this defect has been localized to chromosome band 6q23. Neonatal course is usually uneventful. These patients present with progressive spastic diplegia or quadriplegia, intellectual impairment, recurrent vomiting, delayed growth, and seizures.
Organic acidemias * Usually these disordersare associated with ketosis and acidosis in addition to hyperammonemia; however, sometimes hyperammonemia dominates the picture, raising the possibility of a urea cycle disorder. The proposed mechanism for hyperammonemia is the accumulation of CoA derivatives of organic acids, which inhibit the formation of N -acetylglutamate, the activator of carbamoyl phosphate synthetase in liver. * Disorders in this group include the following: * Isovaleric acidemia * Propionic acidemia * Methylmalonic acidemia * Glutaric acidemia type II * Multiple carboxylase deficiency * beta-ketothiolase deficiency
Congenital lactic acidosis * These disordersare characterized by increased lactate (10-20 mmol/L), increased lactate/pyruvate ratio, metabolic acidosis, and ketosis. Hyperammonemia and citrullinemia have been observed in some cases. * This group includes the following: * Pyruvate dehydrogenase deficiency * Pyruvate carboxylase deficiency * Mitochondrial disorders
Fatty acid oxidation defects * Acyl CoA dehydrogenase deficiency: Deficiency of medium- or long-chain acyl CoA dehydrogenase leads to defective beta-oxidation of fats. Patients present with severe hypoglycemia. Some patients have modest hyperammonemia secondary to hepatic dysfunction. * Systemic carnitine deficiency: Carnitine is required for transport of long-chain fatty acids into mitochondria. Its deficiency causesnonketotic hypoglycemia, increase in liver transaminases, and modest elevation of ammonium level. Patientsmay have muscle weakness, cardiomyopathy, hepatomegaly, and/or growth retardation.
Dibasic amino acid transport defects * Lysinuric protein intolerance (LPI): This disorder is characterized by a defect in membrane transport of cationic amino acids lysine, arginine, and ornithine. The mechanism for hyperammonemia is the deficiency of ornithine and arginine. Citrulline, when given orally, abolishes the hyperammonemia as it is transported by a different mechanism in the intestine. Affected individuals havenormal neurologic development when adequately treated. * Hyperammonemia-hyperornithinemia-homocitrullinuria (HHH): These infants present in the first few weeks of life with seizures, feeding difficulty, and altered level of consciousness. A defect in transport of ornithine from cytosol into mitochondria causes hyperornithinemia, and disruption of the urea cycle causes hyperammonemia. In the absence of ornithine, mitochondrial carbamoyl phosphate reacts with lysine to form homocitrulline.
Transient hyperammonemia of the newborn * This disorder is seen in premature infants. Onset of symptoms is on the first or second day of life before introduction of any protein. * These infants have seizures, decreased consciousness, fixed pupils, and loss of oculocephalic reflex. Because of these clinicalfindings, conditions like severe hypoxic-ischemic encephalopathy and intracranial hemorrhageare considered first. * Hyperammonemia is marked and is treated with hemodialysis. * Twenty to thirty percent of these infants die, and about 35-45% have abnormal neurologic development. * Possible mechanism is slow maturation of the urea cycle function.
Asphyxia
* Hyperammonemia has been observed in newborns with severe perinatal asphyxia. High levels of ammoniaare found within the first 24 hours of life. * Increased ammonia is usually accompanied by elevated serum glutamic oxaloacetic transaminase (SGOT).
Reye syndrome * Reye syndrome is an acquired disorder usually occurring after a viral infection (particularly influenza A or B or varicella). Statistically, it has some association with aspirin ingestion. In one case, Reye-like syndrome was reported due to food poisoning caused by Bacillus cereus.[7] * Patients present with symptoms and signs of cerebral and hepatic dysfunction—vomiting, altered level of consciousness, seizures, cerebral edema, and hepatomegaly without jaundice. * Laboratory studiesreveal marked increases in liver transaminases, hyperammonemia, and lactic acidosis.
Drugs
* Valproate * Therapy with valproate is associated with hyperammonemia, usually less than 2-3 times the upper limit of the reference range. It is frequent in patients on combination therapy for epilepsy. The mechanism is decreased production of mitochondrial acetyl CoA, which causes decrease in N-acetylglutamate, an activator of carbamoyl phosphate synthetase. Thus, patients with partial enzyme deficienciesmay be at increased risk of developing symptomatic hyperammonemia during treatment with valproate. * Valproate can also cause a carnitine deficiency, which leads to B-oxidation impairment followed by urea cycle inhibition. Administration of carnitine has been shown to speed the decrease of ammonia in patients with valproic acid–induced encephalopathy, but further studiesare needed to clarify the therapeutic and prophylactic role of carnitine and optimal regimen of administration.[8] Asymptomatic hyperammonemia has been reported as a frequent, but transient finding following intravenous loading dose of valproic acid.[9] * A topiramate/valproate-induced hyperammonemic encephalopathy was reported in patients on dual therapy, which is reversible with cessation of either medication. The hypothesized mechanism of the encephalopathy is a synergy between valproate and topiramate.[10, 11] * Carbamazepine-induced hyperammonemia is rarely encountered.[12] * Chemotherapy: Acute hyperammonemia has been reported after high-dose chemotherapy such as 5-fluorouracil, resulting in a high mortality rate. * Salicylate: Intoxication with aspirin can presentfindings similar to Reye syndrome with an initial respiratory alkalosis and hyperammonemia.
Liver disease * This is a common cause of hyperammonemia in adults. Itmay be due to an acute process, for example, viral hepatitis, ischemia, or hepatotoxins. * Chronic liver diseases that can cause hyperammonemia include the following: * Biliary atresia, Alpha1-antitrypsin deficiency, Wilson disease * Cystic fibrosis, Galactosemia , Tyrosinemia
Renal
* Urinary tract infection with a urease-producing organism, such as Proteus mirabilis, Corynebacterium species, or Staphylococcus species, can produce a hyperammonemic state. * This usually happens in association with high urinary residuals and an alkaline pH.
Other causes * Herpes infection: Hyperammonemia, in association with neonatal herpes simplex pneumonitis, has been reported. The increase in ammonia level resulted from protein catabolism caused by prolonged hypoxia. * Parenteral hyperalimentation: Increased nitrogen load in patients receiving parenteral alimentation can cause hyperammonemia. * Hyperammonemia has been reported in patients with thyroid disease and Hashimoto encephalopathy.[13, 14] * Hyperammonemia is a rare but severe complication of multiple myeloma and is associated with high mortality.[15]
Other diagnostic considerations * The clinical presentation of hyperammonemia in the neonatal period isnonspecific and merely indicates that the infant is in distress; therefore, disorders such as sepsis, intracranial hemorrhage, cardiac disease, and gastrointestinal obstruction should be ruled out with appropriate laboratory and imaging studies. Plasma ammonium level should be determined in all such scenarios. Once it is found to be elevated (ie, >200 µmol/L), then aspecific diagnosis can be made with the help of the following laboratory studies: * Plasma and urinary amino acids * Urinary organic acids * Serum glucose * Arterial blood gases * Bicarbonate * Lactate * Citrulline * Urinary ketones * Urinary orotate * Hyperammonemia, along with acidosis, ketosis, and a low bicarbonate level, is suggestive of an organic acidemia. In addition, hyperglycinemia and hypoglycemia alsoare seen in some organic acidemias. Hyperammonemia, in addition to acidosis, ketosis, and increased lactate and citrulline, indicates pyruvate carboxylase deficiency. * Hyperammonemia with respiratory alkalosis is caused by a urea cycle defect or transient hyperammonemia of the newborn. Plasma citrulline level can help to localize the defect within the urea cycle. In AS deficiency (ie, citrullinemia), plasma citrulline level is very high (>1000 µmol/L). In AL deficiency (ie, argininosuccinic aciduria), citrulline level is increased moderately (100-300 µmol/L). Trace levels of citrulline or complete absence suggests deficiency of CPS or OTC. Determination of urinary orotate, which is elevated in OTC deficiency, differentiates the two. Thus, CPS deficiency is a diagnosis of exclusion and can be confirmed by enzyme assay on a tissue specimen. NAGS deficiency resembles CPS deficiency and also requires a liver biopsy for a definitive diagnosis. * The presence of hyperammonemia within the first 24 hours in a premature infant withnormal to mildly elevated citrulline levels represents transient hyperammonemia of the newborn. * Differential diagnosis of late-onset hyperammonemia * In a child presenting with hyperammonemia, the differential diagnosis includes all the disorders already mentioned, as well as some other conditions. The additional laboratory studies for these disorders include liver function tests, plasma carnitine, and arginine. * Hyperammonemia with metabolic acidosis, ketosis, markedly elevated hepatic transaminases, and hyperbilirubinemia suggests liver disease and hepatotoxicity. * A similar laboratory profile without hyperbilirubinemia is seen in Reye syndrome or systemic carnitine deficiency. * In the absence of acidosis or ketosis, the possibilitiesare a urea cycle defect or an amino acid transport defect. Determination of citrulline and urinary orotate would help to diagnose thespecific enzyme deficiency, except for argininemia, in which citrulline level is within the reference range but plasma arginine level is raised markedly (>500 µmol/L). * If serum levels of citrulline and arginineare within reference ranges, amino acid transport defects should be considered. Increased urinary excretion of lysine is seen in LPI, whereas in HHH syndrome, plasma ornithine level is elevated along with increased urinary homocitrulline.
Differentials
* Ataxia with Identified Genetic and BiochemicalDefects * Diseases of Tetrapyrrole Metabolism: Refsum Disease and the Hepatic Porphyrias * Disorders of Carbohydrate Metabolism * EEGin Dementia and Encephalopathy * Inherited Metabolic Disorders * Metabolic Disease & Stroke: Homocystinuria/Homocysteinemia * Metabolic Disease & Stroke: Methylmalonic Acidemia * Syncope and Related Paroxysmal Spells

Laboratory Studies * The following tests should be performed after a patient is found to be hyperammonemic: * Arterial blood gas analysis: This study determines acid-base status; respiratory alkalosis strongly suggests a urea cycle defect; it is the result of hyperventilation due to stimulation of the central respiratory drive. * Serum amino acid tests * Glutamineand alanine levels are increased in all urea cycle defects except for arginase deficiency. * Citrulline level is decreased mildly in CPS/NAGSand OTC deficiencies but increased markedly in AS deficiencyand moderately in AL deficiency. * Arginine level is increased markedly in arginase deficiency but decreased mildly in all the other enzyme deficiencies of the urea cycle. * Argininosuccinic acid level is increased markedly in AL deficiency. * Urinary orotic acid tests: The level is increased markedly in OTC deficiencyand mildly in other enzyme deficiencies except for CPS/NAGS deficiency, in which it is decreased mildly. * Urinary ketone tests: Presence of ketosis indicates an organic acidemia. * Plasmaand urinary organic acid tests: These levels screen for the presence of an organic acidemia that may be causing the hyperammonemia. * Enzyme assays: Assays performed on tissue specimens obtained by percutaneous liver biopsy can determine diagnosis in cases of CPS, NAGS,and OTC deficiency. * Heterozygote identification in OTC-deficient pedigrees * Allopurinol loading test: This test establishes the carrier status of women at risk for OTC deficiency. After a loading dose of allopurinol, urinary orotidine excretion is measured; it is increased greatly in carriers. * DNA analysis: Several techniques are available to determine the presence of a mutation at the OTC locus. * Antenatal diagnosis: All urea cycle defects can be diagnosed antenatally by different techniques.
Imaging Studies * Neuroimaging: CT or MRI ofthe brain may show cerebral edema in acute hyperammonemia.The classic MR finding in patientswith chronic liver disorders is hyperintense signal inthe globus pallidum on T1 weighted images due to increased tissue concentration of manganese. * MR spectroscopy: This shows an elevated glutamine/glutamate peak coupledwith decreased myoinositoland choline signals.[16, 17] * Multiple strokelike lesions have been recently reported as MRI finding in a patientwith hyperornithinemia-hyperammonemia-homocitrullinuria.[18] * Newer imaging technique involving diffusion tensor imaging reveals damage to corticospinal tracts in patientswith arginase deficiency.[19]
Histologic Findings
The most consistent neuropathologic change in encephalopathieswith hyperammonemia is prominent Alzheimer type II astrogliosis.
Medical Care
The aims are to correct biochemical abnormalities and ensure adequate nutritional intake. Treatment involves compounds that increasethe removal of nitrogen waste.These compounds convert nitrogen into products other than urea, which arethen excreted; hence,the load onthe urea cycle is reduced.The first compounds to be used were sodium benzoate and arginine. Later, phenylacetate was used, which has now been replaced by phenylbutyrate. * Treatment of neonatal hyperammonemic coma * Protein intake should be stopped. * Calories should be supplied by giving hypertonic glucose. * Hemodialysis should be started promptly in all comatose neonates with plasma ammonium levels greater than 10 times reference range. Plasma ammonium levels are reduced quickly andthe total dialysis time is shorter with hemodialysis than with peritoneal dialysis. Continuous arteriovenous or venovenous hemofiltration may be used as an alternative method.[20] * Intravenous benzoate and phenylacetate should be started oncethe plasma ammonium level falls to 3-4 timesthe upper limit ofthe reference range. * Intravenous arginine should be provided. * Corticosteroids are not indicated forthe management of increased intracranial pressure in hyperammonemia becausethey induce negative nitrogen balance. * Treatment of intercurrent hyperammonemia * Patients with urea cycle defects may present with episodes of hyperammonemia secondary to increased protein intake, increased catabolism, or noncompliance withtherapy. This should be recognized early and treated as an emergency. * Treatment should be started ifthe plasma ammonium level is 3 timesthe reference level. * All nitrogen intake should be stopped. * High parenteral intake of calories from 10-15% glucose and intralipids should be provided. * Intravenous infusion of sodium benzoate and phenylacetate should be started. * Plasma ammonium levels should be checked atthe end ofthe infusion and every 8 hours. * Oncethe ammonia level is near normal, oral medication should be started. * Ifthe level does not decrease in 8 hours, hemodialysis should be started. * Osmotic demyelination syndrome has been reported as a potential serious complication of standardtherapy for hyperammonemia in patients with ornithine transcarbamylase deficiency.[21]
SurgicalCare
* Liver transplantation:The main goal of liver transplantation isto correctthe metabolic error. In one recent study of liver transplantation in patients with defects causing hyperammonemia, metabolic errors were corrected in all patients, and requirements for medication and dietary restriction were eliminated. Neurologic outcomes correlated closely with status priorto transplantation. Thus, liver transplantation is a good option for patients with urea cycle defects who have not suffered major brain injury. * Liver cell transplantation, administered as multiple intraportal infusions of cryopreserved hepatocytes, has been reported as a potentially less invasive alternative or bridgingto liver transplantation.[22, 23]

Consultations * Nephrologist for hemodialysis * Dietitianto help withthe dietary management and educationofthe family * Geneticist for possible testingof family members andto provide genetic counseling
Diet
Dietary management consistsofthe following: * Low protein intake: Current recommendation is 0.7 g/kg/dayof protein and 0.7 g/kg/dayof essential amino acid mixture. Duringthe first 6 months, an infant maytolerate 1.5-2 g/kg/dayof protein. * Arginine supplementation: Arginine is an essential amino acid in patients with urea cycle defects. In neonates, citrulline can be given as a sourceof arginine as it gives one less nitrogen atom; in late-onset cases, however, arginine is acceptable becauseof increased nitrogentolerance. * Providing enough caloriesto meet energy requirements
Activity
Restricting physical activityofthese children is not necessary; however, caloric intake should be sufficientto avoid protein breakdown.
Medication Summary
The medical management of urea cycle disorders used to be limited to dietary modifications, which were not sufficient in many patients. Introduction of compounds that promote alternate pathways for nitrogen excretion was a big breakthrough. As nitrogenis converted to compounds other than urea, the load on the urea cycleis reduced.
Urea cycle disorder treatment agents
ClassSummary
This group consistsof sodium benzoate, sodium phenylacetate, and sodium phenylbutyrate.These drugs lower blood ammonia concentrations by conjugation reactions involving acylationof amino acids. Sodium phenylbutyrateis a prodrug andis metabolized to phenylacetate. Phenylacetatethen conjugates with glutamine to form phenylacetylglutamine, whichis then excreted bythe kidneys. On a molar basis, 1 moleof phenylacetate removes 2 molesof nitrogen.
Animal studies have demonstrated that L ornithine, whichis used as a substrate for glutamine synthesis, combined with phenylacetate, acted synergistically and produced a sustained reduction in ammonia and brain water in cirrhotic rats.[24]
Sodium benzoate and sodium phenylacetate (Ucephan) Benzoate combines with glycine to form hippurate, whichis excreted in urine. One moleof benzoate removes 1 moleof nitrogen.
View full drug information
Sodium phenylbutyrate (Buphenyl) Phenylacetate was introduced after benzoate but now has been replaced by phenylbutyrate because former has bad odor. Adverse effects include menstrual disturbances (23%of patients), anorexia, pH disturbance, hypoalbuminemia, disturbance in phosphate metabolism, Fanconi syndrome, bad taste, andoffensive body odor. Available in powder and tablet forms.
Sodium phenylbutyrate (Rx) - Buphenyl, phenylbutyrate sodium * Class: Urea Cycle Disorder Treatment Agents Pediatric Dosing & Uses: Dosing Forms & Strengths
Tablet: 500mg powder, oral: 3g/tsp
Urea Cycle Disorder
>20 kg: same as adult
<20 kg: 450-600 mg/kg/day divided q4 -6hr PO (solution only)
No more than 20 g/day
Administration: Take with food
Mix powder with solid or liquid food but NOT acidic beverages (eg, orange
Adverse Effects
>10%: Amenorrhea/dysmenorrhea (23%)
Hypoalbuminemia (11%), Metabolic acidosis (14%), 1-10%: Anemia, Decr appetite
Hypophosphatemia, Hypernatremia, Hyperuricemia, Hypokalemia, Leukopenia
Strong body odor, Thrombocytopenia,

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