INTRODUCTION — The urea cycle is the metabolic pathway that transforms nitrogen to urea for excretion from the body (figure 1). Deficiency of an enzyme in the pathway causes a urea cycle disorder (UCD). The UCDs are:
●Carbamoyl phosphate synthetase I (CPSI) deficiency (MIM #237300)
●Ornithine transcarbamylase (OTC) deficiency (MIM #311250)
●Argininosuccinate synthetase (ASS) deficiency (also known as classic citrullinemia or type I citrullinemia [CTLN1]; MIM #215700)
●Argininosuccinate lyase (ASL) deficiency (also known as argininosuccinic aciduria; MIM #207900)
●N-acetyl glutamate synthetase (NAGS) deficiency (MIM #237310)
●Arginase deficiency (also known as argininemia, MIM #207800)
UCDs, except for arginase deficiency, result in hyperammonemia and life-threatening illnesses. Survivors of the metabolic decompensation frequently have severe neurologic injury that correlates with the cumulative duration of hyperammonemia. Prompt recognition and treatment are needed to improve outcome.
The management of UCDs is discussed here. The clinical features and diagnosis of UCDs are discussed separately. A general overview of inborn errors of metabolism is also presented separately. (See "Urea cycle disorders: Clinical features and diagnosis" and "Inborn errors of metabolism: Classification" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management".)
INITIAL MANAGEMENT OF METABOLIC DECOMPENSATION
Presentation — The typical presentation, which appears after a protein load and usually occurs during episodes of increased catabolism, is reviewed in greater detail separately. In brief, initial signs may include somnolence, inability to maintain normal body temperature, and poor feeding, usually followed by vomiting, lethargy, and coma. Other findings include early central hyperventilation, later hypoventilation, abnormal posturing, and seizures. Early signs and symptoms in older children and adults can include headache, anorexia, ataxia, and behavioral abnormalities. (See "Urea cycle disorders: Clinical features and diagnosis", section on 'Typical presentation' and "Urea cycle disorders: Clinical features and diagnosis", section on 'Atypical presentation'.)
Overview of initial approach — Neurologic abnormalities and impaired cognitive function are significantly correlated with the duration of hyperammonemia and encephalopathy [1,2]. Thus, normalization of blood ammonia levels is the management priority. Treatment should be initiated as soon as a UCD is suspected and should proceed concurrently with the diagnostic evaluation [3-6]. (See "Urea cycle disorders: Clinical features and diagnosis", section on 'Diagnosis'.)
Symptomatic patients with hyperammonemia should be cared for in a center with established experience in the diagnosis and treatment of metabolic disorders, including hemodialysis. Optimally, care should be directed by a biochemical geneticist experienced in the management of inborn errors of metabolism.
The initial approach to treatment consists of the following:
●Rehydrate and maintain good urine output without overhydration
●Remove nitrogen (ammonia) from the body using medications and/or hemodialysis
●Stop protein intake and minimize catabolism
●Stimulate anabolism and uptake of nitrogen precursors by muscle
If acute management to control hyperammonemia extends beyond 24 to 48 hours due to an extended catabolic state, the above interventions are continued with the exception that protein is reintroduced via total parenteral nutrition and/or continuous enteral feeds, if possible.
Intravenous (IV) access, preferably via a central catheter, should be established for blood sampling and for the administration of fluids and medications.
Respiratory status should be closely monitored because clinical condition can deteriorate rapidly. Patients with respiratory failure should receive assisted ventilation because increased work of breathing results in higher caloric demands, leading to increased catabolism and nitrogen accumulation. (See "Acute respiratory distress in children: Emergency evaluation and initial stabilization" and "Overview of mechanical ventilation in neonates" and "Overview of initiating invasive mechanical ventilation in adults in the intensive care unit" and "Modes of mechanical ventilation".)
Most newborns with clinical features of a UCD are treated with broad-spectrum antibiotics because sepsis is suspected. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates".)
Fluid management — Symptomatic patients typically are volume depleted because of a history of poor feeding and/or recurrent vomiting. Reduced tissue perfusion can further increase protein catabolism and nitrogen load and lead to increased ammonia concentrations. In addition, pharmacologic treatment of UCDs requires good kidney function. Thus, repletion of intravascular volume is a priority. However, the fluid infusion rate should be adjusted carefully because overhydration may worsen the intracellular cerebral edema caused by hyperammonemia.
Standard bolus infusion with normal saline is appropriate in patients with acute hypovolemia. The composition of maintenance fluid depends upon whether pharmacologic therapy to remove ammonia is implemented. Saline infusion subsequent to acute fluid resuscitation should be minimized if pharmacologic therapy is used because of the high saline content of nitrogen scavenging medications. Instead, IV fluids should consist of 10 percent dextrose in water (D10W), although significant and prolonged hyperglycemia should be avoided. In addition, D10W is supplemented with sodium and potassium (2 mEq of each/100 mL) if arginine hydrochloride infusion is used. If sodium phenylacetate-sodium benzoate infusion is given, then D10W is supplemented with potassium chloride, which adds no additional sodium. If both arginine hydrochloride and sodium phenylacetate-sodium benzoate are used, then D10W is supplemented with 2 mEq/mL of potassium acetate. The potassium counteracts the hypokalemic effects of the large sodium load (assuming normal urine output), while the acetate base counteracts the potential acidosis due to the large chloride load. Calculation of total maintenance IV fluids should take into account the amount of fluid delivered with pharmacologic therapy. The total volume provided should be 1 to 1.5 times daily maintenance fluid requirements per 24 hours. (See 'Pharmacologic therapy' below.)
Ammonia removal — Excessive ammonia is removed by hemodialysis and medications. Hemodialysis is the quickest and most efficient method. Newborns with acute (less than 24 to 48 hours' duration) and severe hyperammonemia should be cared for in a center capable of performing hemodialysis. Exchange transfusion does not effectively remove ammonia and should not be used . IV fluid administration, rather than hemodialysis, is often sufficient therapy in patients with arginase deficiency who present with milder hyperammonemia .
Hemodialysis — Hemodialysis should be started as soon as possible after hospital admission of a patient with severe hyperammonemia. Indications include an ammonia level that is rapidly increasing, acute hyperammonemia that is resistant to initial drug therapy, and/or ammonia that is persistently above the range of 350 to 400 micromol/L . Continuous arteriovenous or venovenous hemodialysis (CAVHD or CVVHD) with flow rates >40 to 60 mL/min is optimal. Some centers use extracorporeal membrane oxygenation (ECMO) with hemodialysis. This technique provides very high flow rates (170 to 200 mL/min) and rapidly reduces ammonia levels but with greater morbidity associated with surgical vascular access . Hemodialysis for hyperammonemia is in greater detail separately. (See "Intermittent dialysis and continuous modalities for patients with hyperammonemia".)
If these procedures are not available, continuous venovenous hemofiltration (CVVH; also known as detoxification) may be used. This method is less desirable as an initial treatment, although it can be used effectively between hemodialysis treatments to continue removing ammonia. Peritoneal dialysis is the least acceptable method because clearance of ammonia is very slow and detoxification may take several days. It should be used only if no other option is available . (See "Continuous kidney replacement therapy in acute kidney injury", section on 'Definition of CKRT modality' and "Prescribing peritoneal dialysis".)f
Ammonia concentration is measured hourly during dialysis. Hemodialysis is stopped when the ammonia concentration has dropped below 200 micromol/L because it appears to have little effect below this level. However, plasma ammonia may increase again (rebound) because of the delay in the effect of nitrogen scavenging medications and the ongoing catabolism that continues to produce waste nitrogen. Reversal of the catabolic process typically takes 24 to 48 hours. It may take longer if infection is present. Thus, hourly monitoring of ammonia levels is continued until ammonia levels have stabilized below 200 micromol/L for at least 24 hours after stopping dialysis, after which the frequency of measurements can be reduced to every four hours. During this period, hemofiltration can be used to clear the newly produced nitrogen. Dialysis catheters should be kept in place until ammonia levels have been stable for at least 24 hours.
Pharmacologic therapy — Pharmacologic therapy of hyperammonemia consists of administration of a combination preparation of sodium phenylacetate-sodium benzoate. Most patients are also given arginine, whereas citrulline and carglumic acid are used in only a few UCDs.
A conservative approach of only initial IV fluid rehydration with cessation of protein intake is reasonable when peak hyperammonemia is <200 micromol/L and when the duration of hyperammonemia is less than 24 hours. New oral medications usually are not started in these patients until ammonia levels are falling, but existing oral medications typically are continued in these patients if they are not vomiting. However, if hyperammonemia is persistent, >200 micromol/L, or showing rapid increase, then pharmacologic therapy to remove ammonia should be instituted immediately:
●For proximal UCDs (N-acetyl glutamate synthetase [NAGS], carbamoyl phosphate synthetase I [CPSI], and ornithine transcarbamylase [OTC] deficiencies), initiate IV arginine hydrochloride (low maintenance dose), IV sodium phenylacetate-sodium benzoate, and oral citrulline.
●For NAGS deficiency, initiate oral carglumic acid.
●For distal UCDs (argininosuccinate synthetase [ASS] and argininosuccinate lyase [ASL] deficiencies), initiate IV arginine hydrochloride (high maintenance dose) and IV sodium phenylacetate-sodium benzoate.
●For arginase deficiency, initiate IV sodium phenylacetate-sodium benzoate.
●If the diagnosis is not known initially, initiate IV sodium phenylacetate-sodium benzoate and IV arginine hydrochloride (low maintenance dose).
Pharmacologic therapy is held if the patient is started on dialysis and is restarted immediately after dialysis is discontinued.
Specific therapies — The mechanism of action, dosing, efficacy, and side effects of each therapy are reviewed here.
●Sodium phenylacetate-sodium benzoate – A combined preparation of sodium phenylacetate-sodium benzoate was approved by the US Food and Drug Administration (FDA) in February 2005 for parenteral delivery. These drugs scavenge ammonia by creating an alternate pathway to excrete nitrogen precursors . Phenylacetate combines with glutamine to form phenylacetylglutamine, and benzoate combines with glycine to form hippurate [13,14]. These conjugation products are water soluble and are excreted in the urine. Thus, adequate kidney function is essential . Disposal of glutamine and glycine reduces the total nitrogen pool. Pharmacokinetics for the biochemical conversions may vary from patient to patient. Signs of toxicity, including altered mental status, nausea and vomiting, and metabolic acidosis, should be monitored during treatment. Drug levels can be obtained in specialized labs, but such testing is usually not accessible in the emergency treatment scenario of initial management.
For patients who weigh ≤20 kg, we use a loading dose of 500 mg/kg (250 mg/kg of each drug) in a volume of 25 to 35 mL/kg of 10 percent dextrose solution infused over 90 minutes. For patients who weigh >20 kg, dosing is based upon body surface area; the loading dose is 11 g/m2 (ie, 5.5 g/m2 of each drug). The loading dose may be repeated in the rare case that a patient does not respond to dialysis. Drug levels should be monitored in this circumstance to avoid toxicity, including death .
Maintenance infusion of sodium phenylacetate-sodium benzoate (500 mg/kg per 24 hours for patients <20 kg, 11 g/m2 per 24 hours as a continuous infusion for patients >20 kg) is started when the loading dose is completed and is administered in the same volume as the loading dose (25 to 35 mL/kg). The maintenance infusion is continued until oral sodium phenylbutyrate can be tolerated. (See 'Management after stabilization' below.)
The effect of treatment with IV sodium phenylacetate-sodium benzoate on survival in patients with UCDs was evaluated in a 25-year (1980 to 2005) nonrandomized, uncontrolled, open-label study at 118 hospitals . The study included 299 patients in whom there were 1181 episodes of hyperammonemia. Dialysis was used in addition to sodium phenylacetate-sodium benzoate for 60 percent of episodes of hyperammonemia in patients <30 days of age and for 7 percent of episodes of hyperammonemia in patients >30 days of age. Neurologic outcome was not evaluated. Overall survival was 84 percent . Survival following episodes of hyperammonemia was 96 percent (73 percent in patients <30 days of age, 98 percent in patients >30 days of age, and 81 percent in patients who were comatose at the time of admission). By way of comparison, survival in 217 patients from a single institution who did not receive alternative pathway pharmacologic therapy was 16 percent for those with neonatal-onset UCD and 72 percent for those with late-onset UCD .
Adverse effects of sodium phenylacetate-sodium benzoate therapy occurred in approximately one-half of patients. Most of these were metabolic (eg, hypokalemia, hyperchloremia, acidosis), neurologic (eg, seizures), or respiratory (eg, respiratory distress or failure) . Among the 49 patients who died, 13 received higher than recommended doses of sodium phenylacetate and sodium benzoate.
●Arginine – IV arginine hydrochloride is used as part of the initial management of metabolic decompensation in all forms of UCD except known arginase deficiency. Enzyme deficiencies in the urea cycle (with the exception of arginase deficiency) prevent the formation of arginine, thus rendering it an essential amino acid . Arginine deficiency results in a catabolic state that stimulates further mobilization of nitrogen from protein breakdown. In OTC, ASS, and ASL deficiencies, arginine also is needed to generate urea cycle intermediates, including ornithine, citrulline, and argininosuccinic acid. In case reports and observational studies, these water-soluble compounds were formed and excreted when supplemental arginine was provided, resulting in additional removal of ammonia [20-22].
In the absence of a diagnosis of the specific form of UCD and/or for patients ≤20 kg, the loading dose is 200 mg/kg dissolved in 25 to 35 mL/kg of 10 percent dextrose solution infused over 90 minutes. For patients >20 kg with a known diagnosis of a specific UCD other than arginase deficiency, the loading dose is 4 g/m2.
The maintenance dose is started after the loading dose. In CPSI or OTC deficiency, or if the specific UCD is not yet identified, the IV maintenance dose is 200 mg/kg per 24 hours for patients ≤20 kg and 4 g/m2 per 24 hours for patients >20 kg. For ASS and ASL deficiency, the maintenance dose is 600 mg/kg per 24 hours for patients ≤20 kg and 12 g/m2 per 24 hours for patients >20 kg. This higher dose of arginine increases the generation of citrulline (in ASS deficiency) and argininosuccinic acid (in ASL deficiency), which enhances nitrogen excretion.
Blood pressure should be monitored since high doses of IV arginine can decrease blood pressure. Patients should also be monitored for hyperchloremic acidosis.
●Citrulline – In OTC or CPSI deficiency, small oral doses of citrulline (150 to 200 mg/kg per 24 hours for patients ≤20 kg and 3 to 4 g/m2 per 24 hours for patients >20 kg) also are provided because incorporating aspartate nitrogen may improve clearance as urea in disorders upstream of ASS. In one retrospective study, patients treated with L-citrulline had reduced ammonia levels and improved weight gain that was most likely due to increased protein intake . Citrulline should not be given if the diagnosis is unknown, because citrulline levels are elevated in ASS and ASL deficiencies.
●Carglumic acid – Carglumic acid (Carbaglu), which was previously available outside the United States, was approved by the US FDA in March 2010 for the treatment of hyperammonemia due to NAGS deficiency [24,25]. Carglumic acid is able to activate the first enzyme of the urea cycle (CPSI), leading to rapid reduction of plasma ammonia to normal levels. It is used for both acute and chronic hyperammonemia due to NAGS deficiency. Sodium phenylacetate-sodium benzoate is used in addition to carglumic acid if the hyperammonemia is severe; otherwise, carglumic acid can be used alone. The initial dose for acute hyperammonemia ranges from 100 to 250 mg/kg/day orally (prepared as a liquid and divided into two to four doses that are given immediately before meals). The dose is adjusted according to the patient's symptoms and plasma ammonia level.
Laboratory monitoring — Electrolytes should be monitored daily during loading and maintenance infusions of sodium phenylacetate-sodium benzoate because these medications contain high concentrations of sodium and chloride. Sodium phenylacetate administration may cause potassium depletion.
Serum amino acids are measured daily initially, if immediate testing is available, to help assess the efficacy of glutamine removal and to determine if replacement of arginine and/or citrulline is sufficient.
Drugs to avoid — Several drugs can increase serum ammonia levels or protein catabolism in patients with UCDs, while others are ineffective in patients with these disorders:
●Glucocorticoids increase protein catabolism and should not be used routinely.
●Valproic acid inhibits urea synthesis, leading to increased serum ammonia levels . Thus, valproic acid should not be used to treat seizures in patients with a UCD. Seizures may be treated with other antiseizure medications, although correcting the underlying metabolic abnormality is more likely to affect seizure control. (See "Seizures and epilepsy in children: Initial treatment and monitoring".)
●Mannitol is ineffective in treating cerebral edema caused by hyperammonemia due to UCDs. (See "Elevated intracranial pressure (ICP) in children: Clinical manifestations and diagnosis".)
●Drugs that may have direct hepatotoxicity, such as acetaminophen, also should be used cautiously because chronic liver disease is seen in some forms of UCD, particularly ASL deficiency.
Protein restriction — Catabolic stress should be avoided, and protein intake should be restricted to minimize the nitrogen load from protein breakdown or feeding . On the other hand, excessive and prolonged restriction of protein intake will stimulate peripheral mobilization of nitrogen.
In acute hyperammonemia with encephalopathy, oral feedings are discontinued. Calories are provided by IV administration of lipids and glucose, and protein intake is stopped. Protein should not be completely restricted longer than the first 24 to 48 hours after treatment is initiated to avoid protein catabolism resulting in increased circulating nitrogen. If enteral intake of amino acids is not possible because of neurologic compromise, essential amino acids should be administered parenterally. We begin by providing approximately 1.5 to 1.75 g/kg per day of protein as an IV amino acid solution for newborns, with lower levels used for older children and adults. We monitor ammonia levels at least daily and plasma amino acid levels at least every two to three days until the patient is on enteral feeding. (See 'Transition to enteral feeding' below.)
MANAGEMENT AFTER STABILIZATION — Patients who have stabilized (improved mental status and ammonia levels <100 micromol/L) are transitioned from intravenous (IV) therapy to oral medications and enteral feeding. (See 'Pharmacologic therapy' above.)
Transition to enteral feeding — Enteral feeding is initiated as soon as possible based upon mental status and ammonia levels. A nasogastric tube may be needed to ensure appropriate intake. Infants are fed a protein-free formula, such as Mead Johnson 80056 or Ross Formula ProPhree, in conjunction with amino acid mixtures and cow milk-based formulas. One-half of the daily protein requirement is usually given as amino acid mixture and one-half as cow milk protein because the nitrogen load in free amino acid solutions is less than that of complex proteins. The recommended daily protein intake varies with age and ranges from 2 to 2.5 g/kg per day at birth to less than 0.6 to 0.8 g/kg per day in adults. Children with UCDs typically require even less than the recommended daily intake of protein for normal growth. Patients with partial deficiency of a urea cycle enzyme may tolerate greater protein intake. The daily intake of protein and amino acids is adjusted according to the patient's age, growth rate, monitoring nutritional biomarkers (ie, essential amino acid levels in the blood, prealbumin, albumin, and hemoglobin), and clinical course. A dietitian experienced in dietary therapy of inborn errors of metabolism should manage the diet. The daily fluid intake required to maintain a good urine output should also be calculated. (See 'Laboratory monitoring after stabilization' below.)
Sodium phenylacetate, sodium phenylbutyrate, and probably also glycerol phenylbutyrate can selectively depress branched chain amino acids (leucine, valine, and isoleucine) [28,29]. Branched chain amino acid supplementation is warranted in patients who have low concentrations of leucine, valine, and isoleucine and other signs of protein insufficiency (eg, low prealbumin and albumin), especially if they have normal concentrations of other essential amino acids.
Transition to oral medications — Once the IV amino acid infusion is tolerated (ie, ammonia levels are normal or consistently <100 micromol/L and mental status has returned to baseline) or the patient has responded quickly and has moved directly to enteral feeding, we discontinue the IV infusion of sodium phenylacetate-sodium benzoate and administer oral sodium phenylbutyrate (400 to 600 mg/kg per 24 hours for patients ≤20 kg and 9 to 13 g/m2 per 24 hours for patients >20 kg) or, in patients ≥2 months of age, oral glycerol phenylbutyrate (4.5 to 11.2 mL/m2/day divided in three equal doses) [30-32]. Citrulline (170 mg/kg per day orally) is continued in patients with ornithine transcarbamylase (OTC) or carbamoyl phosphate synthetase I (CPSI) deficiency; patients with argininosuccinate synthetase (ASS) or argininosuccinate lyase (ASL) deficiency are switched from the arginine hydrochloride solution used in IV therapy to arginine base (500 mg/kg per day orally); and the dose of carglumic acid is typically reduced to <100 mg/kg/day in patients with N-acetylglutamate synthase (NAGS) deficiency. (See 'Laboratory monitoring after stabilization' below.)
Sodium phenylbutyrate is converted to phenylacetate, which promotes urinary clearance of nitrogenous waste. Glycerol phenylbutyrate is a pre-prodrug of phenylacetate. It requires pancreatic lipase conversion into phenylbutyrate, which is then oxidized into phenylacetate. Thus, it acts as a slow-release form of sodium phenylbutyrate, achieving more stable control of ammonia levels over a 24-hour period. In addition, it may offer advantages with regards to tolerability and palatability since it is a colorless and tasteless oil with no sodium content. However, its use is contraindicated in infants under two months of age due to immature pancreatic exocrine function that could lead to insufficient drug metabolism. Glycerol phenylbutyrate was noninferior to sodium phenylbutyrate in controlling ammonia levels over 24 hours in two randomized, crossover trials of patients with UCD (one with 45 adults and 20 children six years of age and older  and the other with 15 children less than six years of age ). In an uncontrolled 12-month extension study, patients showed improved measures of executive functioning compared with baseline on enrollment . A direct conversion of dosing can be calculated for patients already on sodium phenylbutyrate: Total daily dose glycerol phenylbutyrate (mL) = 0.8 x total daily dose sodium phenylbutyrate (grams).
Chronic administration of sodium phenylbutyrate is associated with significant gastrointestinal side effects (eg, gastritis). Therefore, proton pump inhibitors (PPIs) such as omeprazole are suggested, although this needs to be balanced with increasing concerns regarding long-term use of PPIs. Significant gastrointestinal side effects are not expected with glycerol phenylbutyrate, due to differences in drug metabolism, and therefore PPIs are not needed with this formulation.
Laboratory monitoring after stabilization — During the transition to food protein, we measure serum levels of essential amino acids (eg, branched chain amino acids, phenylalanine, lysine), which reflect adaptation to the protein intake during the previous 48 hours. The target goal is the low-normal range for these essential amino acids. Samples are obtained three to four hours after feeding and repeated every two to three days. Prealbumin levels, which reflect protein intake during the previous two weeks, also can be monitored. In addition, ammonia levels continue to be monitored. Fasting morning ammonia levels are preferred, when practical, as the magnitude of elevation may correlate with time to next hyperammonemic episode . Otherwise, sampling at the time of amino acid analysis allows for assessing the size of the precursor nitrogen pool. Frequency of monitoring is determined by the age of the patient, growth rate, and frequency of dietary change. For patients on oral phenylbutyrate or glycerol-tri-phenylbutyrate, phenylbutyrate metabolites should be measured.
Dosing of oral phenylacetate is guided by fasting ammonia levels (with a target less than one-half the upper limit of normal), as well as serum phenylacetate and urinary phenylacetylglutamine levels . Ammonia levels are initially measured every 4 to 12 hours, depending on trend and starting level, after transitioning from IV to oral phenylacetate. Testing of ammonia levels can be reduced to every 12 hours after a stable oral drug regimen is established and then daily until the patient is clinically ready for discharge from the hospital.
Both sodium phenylbutyrate and glycerol phenylbutyrate require bioconversion to the active ingredient, phenylacetate. Environmental and/or genetic factors may alter bioavailability. In addition, elevated levels of phenylacetate and phenylbutyrate are associated with neurotoxicity in cancer patients treated with these drugs [37-39]. Thus, plasma phenylacetate and urinary phenylacetylglutamine should be monitored for the first one to two days to assess for potential drug toxicity or reasons for suboptimal clinical response to treatment. Between 60 to 75 percent of the phenylbutyrate dose is converted to phenylacetylglutamine. Twenty-four hour urinary phenylacetylglutamine (or morning spot urine) correlates well with the daily dose of phenylbutyrate and is a good measure of effective bioconversion .
DISCHARGE PLANNING — A stable feeding route should be established before the patient is discharged from the hospital. A gastrostomy tube usually is the most reliable method to control protein and caloric intake routinely and allows administration of additional fluid and medication during viral illnesses. Sodium phenylbutyrate is very bitter, and feeding avoidance may develop when it is given orally. Thus, administration through the gastrostomy tube is preferable. Fundoplication is usually not indicated, and it may disguise clinical signs of hyperammonemia (ie, vomiting).
Adequate time should be available for caregivers to become familiar with the medications, formulas, and dietary supplements. Caregivers must be taught to recognize the signs of early hyperammonemia, including irritability and vomiting. They should know the factors that may trigger a metabolic crisis, such as infection or fever, and understand the importance of preventive measures, such as immunization. There is no association between hyperammonemic episodes and immunizations in children with UCDs , nor is there an associated increased risk of serious adverse events due to immunizations in children with inborn errors of metabolism . Once useful resource for caregivers and patients is the National Urea Cycle Disorders Foundation. (See "Standard immunizations for children and adolescents: Overview", section on 'Routine schedule'.)
LONG-TERM MANAGEMENT — Optimal pharmacologic and dietary treatment should strive to maximize neurodevelopment, prevent intercurrent hyperammonemia and comorbidities (eg, obesity, seizures, feeding disorders, liver disease), and achieve normal fasting glutamine and low-normal fasting ammonia levels in the context of protein sufficiency as evidenced by low-normal levels of prealbumin and essential amino acids. For chronic management, we assess the adequacy of protein intake over the course of weeks to months by measuring serum concentrations of total protein, albumin, and prealbumin, in addition to serial measurements of growth. In stable patients, these measures are assessed every one to three months in newborns and infants <2 years of age, two to three times per year in children 2 to 12 years of age, and yearly in adolescents and adults.
Prevention of subsequent episodes of hyperammonemia — Protein tolerance in affected children usually increases with age. Thus, the greatest risk of hyperammonemia during the first year is due to the protein catabolism associated with viral illnesses. Efforts should be made to avoid infectious exposures, especially during the first year. In addition, patients should receive all standard childhood immunizations. Patients with more severe forms of UCD (eg, null activity proximal UCDs such as ornithine transcarbamylase [OTC] deficiency or citrullinemia type I) should receive prophylaxis against respiratory syncytial virus.
The metabolic specialist should be notified immediately if the patient becomes ill or shows early signs of hyperammonemia. Protein intake can be adjusted during acute illnesses in conjunction with a metabolic dietician. Maintenance of hydration is also indicated for periods of increased metabolic stress, such as prior to surgery or during childbirth [42,43]. When oral intake of medications is limited due to illness, surgery, or more extensive procedures, intravenous (IV) infusion of sodium phenylacetate-sodium benzoate and arginine should be instituted until oral diet and medication are tolerated. Ammonia levels should be monitored during these periods.
The management of subsequent episodes of hyperammonemia is the same as the management for the initial episode. (See 'Initial management of metabolic decompensation' above.)
Monitoring during chronic management — Monitoring during follow-up visits should focus on identifying and preventing overzealous protein restriction, essential amino acid deficiency, and increased nitrogen flux through the body. Monitoring of chronic therapy includes ammonia and plasma amino acid levels, measures of liver function, and nutritional markers (eg, prealbumin, albumin, plasma amino acids, complete blood count). Target levels are low normal for markers of protein sufficiency and normal levels for the other measures. The frequency of monitoring depends upon the age of the patient and can range from every one to two months in a growing infant to once per year in an adult.
Prealbumin and albumin measurement will reflect protein sufficiency over the previous weeks to months, respectively.
Plasma amino acid and ammonia measurements should be performed fasting (prior to a feed or medication dose). A fasting ammonia level ≥1 upper limit of normal (ULN) is associated with an increased risk of hyperammonemic crisis (37 percent over a 12-month period in one study compared with 14 and 12 percent for those with levels 0.5 to <1 ULN and <0.5 ULN, respectively) [35,44].
Measurement of phenylbutyrate metabolites (plasma phenylacetate [PA] and urine phenylacetylglutamine [PAG]) can be performed to guide dose adjustment when there is suboptimal clinical control, as evidenced by recurrent hyperammonemic episodes. The targeted PAA:PAGN ratio is between 0.6 and 1.5, which correlates with blood glutamine levels <1000 uM . A curvilinear relationship was observed between PAA levels and the plasma PAA:PAGN ratio, and a ratio >2.5 (both in mcg/mL) in a random blood draw identified patients at risk for PAA levels >500 mcg/mL, a level associated with toxicity in previous studies . (See 'Laboratory monitoring after stabilization' above.)
Adjunctive treatments — In specific disorders, unique pathophysiologic mechanisms may suggest adjunctive treatments. As an example, some patients with argininosuccinate lyase (ASL) deficiency have evidence of nitric oxide (NO) depletion and show signs of hypertension. This hypertension may be responsive to NO sources such as nitrite. In one case study, nitrite supplementation reversed chronic longstanding hypertension that was unresponsive to other standard forms of therapy . However, randomized trials that confirm efficacy are necessary before routine supplementation can be recommended. Intake of nitrite-rich foods is an acceptable conservative option.
Neurodevelopmental problems are managed with standard interventions such as occupational therapy, physical therapy, and speech therapy.
Liver transplantation — Some patients with UCDs may be candidates for liver transplantation because of the high risk of mortality and neurologic morbidity associated with UCDs [48-54]. The indications for liver transplantation are relative . A careful analysis of the risks and benefits for individual patients should be performed by a multidisciplinary team of clinical biochemical geneticists, transplant surgeons, hepatologists, developmental pediatricians, psychologists, and social workers in conjunction with the family [52,56]. Liver transplantation most often considered as a therapeutic option in infants with carbamoyl phosphate synthetase I (CPSI) or OTC deficiency and in patients with ASL deficiency associated with cirrhosis. However, patients with any form of UCD may be candidates for liver transplantation if medical therapy has failed to prevent recurrent hyperammonemia. Results from one study suggest that developmental outcomes are better in patients who receive early liver transplantation after presenting with acute hyperammonemia of limited duration (<24 hours on average) compared with historical controls .
In a 2015 review of the United Network for Organ Sharing Database, 265 children and 13 adults with UCDs who underwent liver transplant from 1987 to 2010 had overall 1-, 5-, and 10-year survivals of 93, 89, and 87 percent, respectively .
Orthotopic liver transplantation has a higher rate of complications when performed in infancy, primarily due to the size of the graft. However, delaying transplantation can lead to irreversible neurologic complications. Thus, alternative options are under investigation, including liver cell (hepatocyte) and stem cell transplantation . Liver cell transplantation is much less invasive and has been performed successfully in several newborns and older children [57,58]. However, the long-term stability of the transplant is uncertain. Thus, it is primarily used as a bridge to liver transplantation. The feasibility of liver stem cell transplantation is under investigation in animal models.
Gene therapy — Gene therapy was performed for OTC deficiency in 19 patients in a phase-I trial [59-61]. This trial was halted when the 19th patient died from a severe innate immune response to the vector [62-64]. Significant metabolic correction did not occur in the 18 surviving subjects . No further human trials have been performed, but studies in mouse models of UCDs continue.
PROGNOSIS — Mortality and morbidity are still high in UCDs [1,65,66], although survival rates have improved due to earlier diagnosis and improved treatments. In one report from Japan of 216 patients with UCDs treated from 1978 to 1995, 92 presented as newborns, and the remainder had onset at >1 month of age, with a five-year survival of 22 and 41 percent, respectively . In a subsequent report from Japan of 177 patients treated from 1999 to 2009, 77 cases were neonatal onset and 91 cases were late onset, with a five-year survival of 83 and 90 percent, respectively . In a 2014 report from the National Institutes of Health (NIH) Urea Cycle Disorder Consortium that included over 500 patients, there was a 24 percent mortality rate in neonatal-onset disease . The mortality in late-onset disease was 11 percent. By diagnosis, the risk of mortality was greatest in carbamoyl phosphate synthetase I (CPSI) deficiency (42 percent), followed by ornithine transcarbamylase (OTC) deficiency (11 percent), argininosuccinate synthetase (ASS) deficiency (7 percent), and argininosuccinate lyase (ASL) deficiency (6 percent).
Patients often grow poorly and have neurodevelopmental problems . In the earlier Japanese study, 90 percent of the neonatal survivors and 28 percent of late-onset survivors had moderate-to-severe neurodevelopmental deficits . Outcome was associated with the peak blood ammonia concentration during the initial presentation. Severe damage was not seen if the ammonia concentration was <180 micromol/L, whereas patients with levels >350 micromol/L had severe deficits or died. In the second Japanese study, a peak initial ammonia concentration >360 micromol/L was also a marker of poor prognosis, although 18 patients with levels above this cutoff at presentation had normal neurodevelopment .
In another study, long-term neurologic morbidity was related to the duration of hyperammonemia and not to peak ammonia levels . In our experience, the outcome is better in newborns when the duration of hyperammonemia is less than 24 hours.
Specific chronic complications include developmental delay, intellectual disability, learning problems, speech disorder, attention deficit hyperactivity disorder, cerebral palsy, and seizure disorder . Patients should have regular assessment of developmental and cognitive function with management as necessary for any disabilities identified.
Some patients have hepatomegaly that may be associated with abnormal liver function tests, although the mechanism is unknown. Accumulated longitudinal data suggest that liver dysfunction is a common complication of UCDs. The liver dysfunction is not usually clinically significant, although it may be acutely exacerbated during intercurrent illness or metabolic decompensation.
The natural history of these disorders continues to be elucidated. Some long-term morbidity may be unrelated to hyperammonemia and may instead reflect the integration of urea cycle intermediates within intermediary metabolism. As an example, synthesis of nitric oxide (NO) is dependent upon arginine. Thus, dysregulation of NO function is possible in some UCDs in which arginine is depleted, such as ASL deficiency [71,72]. Liver dysfunction can be a significant chronic complication due to deficiency of ASL that leads to depletion of arginine. In the same vein, primary hypertension in these patients is associated with deficient NO production , and neurologic morbidity does not appear to correlate with the frequency of hyperammonemia in patients with ASL deficiency .
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Urea cycle disorders".)
SUMMARY AND RECOMMENDATIONS
●The urea cycle is the metabolic pathway that transforms nitrogen to urea for excretion from the body (figure 1). Urea cycle disorders (UCDs) are caused by deficiency of an enzyme in the pathway: carbamoyl phosphate synthetase I (CPSI), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), N-acetyl glutamate synthetase (NAGS), and arginase. (See 'Introduction' above.)
●The initial approach to treatment of UCDs consists of volume repletion, ammonia removal, protein restriction, and stimulation of anabolism. Respiratory status must be closely monitored. Drugs that increase protein catabolism (eg, glucocorticoids), inhibit urea synthesis (eg, valproic acid), or have direct hepatotoxicity should be avoided. (See 'Initial management of metabolic decompensation' above.)
●Volume repletion is necessary to minimize protein catabolism and nitrogen load and to maintain kidney function. Intravenous (IV) fluids should consist of 10 percent dextrose in water (D10W) with electrolytes. Saline infusion should be minimized (ammonia scavenging medications have a high content of sodium and chloride). (See 'Fluid management' above.)
●Excessive ammonia is removed by dialysis and medications. Hemodialysis is the quickest and most efficient method. Indications for the use of hemodialysis include an ammonia level that is rapidly increasing, acute hyperammonemia that is resistant to initial drug therapy, and/or an ammonia level that is persistently above the range of 350 to 400 micromol/L (Grade 1B). (See 'Ammonia removal' above and 'Hemodialysis' above.)
●Pharmacologic therapy for hyperammonemia consists of initial IV administration of a combination preparation of sodium phenylacetate-sodium benzoate followed by maintenance with oral sodium phenylbutyrate or glycerol phenylbutyrate in all patients except those with NAGS deficiency without severe hyperammonemia. These drugs scavenge ammonia by creating an alternate pathway to excrete nitrogen precursors. Administration of arginine is also necessary for all UCDs except arginase deficiency (argininemia) because deficiencies of these enzymes prevent the formation of arginine, resulting in a catabolic state. Arginine also generates more urea cycle intermediates upstream of the block, and the urinary excretion of these upstream intermediates further acts as a nitrogen disposal pathway. In addition, administration of citrulline may be helpful in OTC and CPSI deficiencies. Citrulline should not be administered if the enzyme deficiency is not known, because citrulline levels are elevated in ASS and ASL deficiencies. Finally, carglumic acid, which can activate the first enzyme in the urea cycle (CPSI) downstream of NAGS, is effective in treating NAGS deficiency. (See 'Pharmacologic therapy' above.)
●Laboratory monitoring during initial treatment for UCD includes measurement of electrolytes (during loading and maintenance infusions of sodium phenylacetate-sodium benzoate), ammonia concentration (hourly during hemodialysis and less frequently once a stable oral regimen has been established), and serum amino acids (daily). (See 'Laboratory monitoring' above.)
●Protein intake is restricted to minimize nitrogen load from protein breakdown or feeding. The recommended daily protein intake varies with age, growth rate, and clinical course. (See 'Protein restriction' above.)
●A stable feeding route should be established before the patient is discharged from the hospital. A gastrostomy tube is the most reliable method to control protein and caloric intake and ensure administration of additional fluid and medication during illness. In addition, parents/caregivers must be familiar with the medications, formulas, dietary supplements, signs of early hyperammonemia, and potential triggers of metabolic crisis. (See 'Management after stabilization' above and 'Discharge planning' above.)
●Chronic management of UCD involves frequent measurement of ammonia and plasma amino acids. Fasting ammonia correlates positively with daily ammonia exposure and with the risk and rate of hyperammonemic crises. Management should strive towards low normal levels of ammonia, normal glutamine levels, and normal essential amino acids in the fasting state. Additionally, in patients treated with phenylbutyrate or glycerol phenylbutyrate, measurement of drug metabolites can be useful in guiding dosing adjustments. (See 'Laboratory monitoring after stabilization' above and 'Monitoring during chronic management' above.)
●Some patients with UCD may be candidates for liver transplantation because of the high risk of mortality and neurologic morbidity associated with UCDs. Liver transplantation is typically reserved for newborns with CPSI or OTC deficiency, patients with ASL deficiency associated with cirrhosis, and patients who have not responded to medical therapy. (See 'Liver transplantation' above.)
●Mortality and morbidity are high in UCDs. Patients often grow poorly and have neurodevelopmental problems. (See 'Prognosis' above.)
2 : Neurologic outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies.
7 : Comparison of exchange transfusion, peritoneal dialysis, and hemodialysis for the treatment of hyperammonemia in an anuric newborn infant.
8 : Comparison of exchange transfusion, peritoneal dialysis, and hemodialysis for the treatment of hyperammonemia in an anuric newborn infant.
10 : Effective hemodialysis and hemofiltration driven by an extracorporeal membrane oxygenation pump in infants with hyperammonemia.
16 : Three cases of intravenous sodium benzoate and sodium phenylacetate toxicity occurring in the treatment of acute hyperammonaemia.
21 : Treatment of inborn errors of urea synthesis: activation of alternative pathways of waste nitrogen synthesis and excretion.
22 : In vivo urea cycle flux distinguishes and correlates with phenotypic severity in disorders of the urea cycle.
28 : Effect of alternative pathway therapy on branched chain amino acid metabolism in urea cycle disorder patients.
29 : Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders.
30 : Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders.
31 : Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders.
32 : Safety and efficacy of glycerol phenylbutyrate for management of urea cycle disorders in patients aged 2months to 2years.
33 : Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate.
34 : Ammonia control in children ages 2 months through 5 years with urea cycle disorders: comparison of sodium phenylbutyrate and glycerol phenylbutyrate.
35 : Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder.
39 : A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies.
45 : Quantitation of phenylbutyrate metabolites by UPLC-MS/MS demonstrates inverse correlation of phenylacetate:phenylacetylglutamine ratio with plasma glutamine levels.
46 : Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio.
47 : Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria.
52 : Developmental outcomes with early orthotopic liver transplantation for infants with neonatal-onset urea cycle defects and a female patient with late-onset ornithine transcarbamylase deficiency.
53 : Current role of liver transplantation for the treatment of urea cycle disorders: a review of the worldwide English literature and 13 cases at Kyoto University.
54 : Liver Transplantation for Urea Cycle Disorders: Analysis of the United Network for Organ Sharing Database.
55 : Evaluation of the pediatric patient for liver transplantation: 2014 practice guideline by the American Association for the Study of Liver Diseases, American Society of Transplantation and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.
57 : One liver for four children: first clinical series of liver cell transplantation for severe neonatal urea cycle defects.
58 : Human heterologous liver cells transiently improve hyperammonemia and ureagenesis in individuals with severe urea cycle disorders.
59 : Correction of ureagenesis after gene transfer in an animal model and after liver transplantation in humans with ornithine transcarbamylase deficiency.
60 : Recombinant adenovirus gene transfer in adults with partial ornithine transcarbamylase deficiency (OTCD).
61 : A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency.
63 : Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer.
71 : Systemic hypertension in two patients with ASL deficiency: a result of nitric oxide deficiency?
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