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Urea cycle disorders: Management

Author: Brendan Lee, MD, PhD
Section Editor: Sihoun Hahn, MD, PhD
Deputy Editor: Elizabeth TePas, MD, MS

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Apr 2020. | This topic last updated: Jan 09, 2018.

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

Neurologic abnormalities and impaired cognitive function are significantly correlated with the duration of
hyperammonemia and encephalopathy [1,2]. Thus, 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'.)

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

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 "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 infants".)

Glucocorticoids increase protein catabolism and should not routinely be used.

Valproic acid decreases urea cycle function and increases serum ammonia levels and should not be used
to treat seizures. Seizures may be treated with other antiepileptic drugs, 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".)

Hyperammonemia may be induced by drugs that inhibit urea synthesis (eg, valproic acid), and these drugs
should be avoided in patients with UCDs [7]. Drugs that may have direct hepatotoxicity also should be used
cautiously.

Symptomatic newborns 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.

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 renal
function. Thus, repletion of intravascular fluid is a priority. However, the fluid infusion rate should be adjusted
carefully because overhydration may worsen the intracellular cerebral edema caused by hyperammonemia.

Intravenous access, preferably via a central catheter, should be established for blood sampling and for the
administration of fluids and medications. Standard bolus infusion with normal saline is appropriate in the
emergent scenario in patients with acute hypovolemia. Saline infusion subsequent to acute fluid
resuscitation should be minimized because of the high saline content of nitrogen scavenging medications.
Instead, intravenous fluids should consist of 10 percent dextrose in water, although significant and
prolonged hyperglycemia should be avoided. (See 'Pharmacologic therapy' below.)

AMMONIA REMOVAL

Excessive ammonia is removed by hemodialysis and medications. Hemodialysis is the quickest and most
efficient method and should be used if ammonia is rapidly increasing, the acute hyperammonemia is
resistant to initial drug therapy, and/or the ammonia is persistently above the range of 350 to 400 micromol/L
[8]. 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 [9]. Intravenous fluid administration, rather than hemodialysis, is often
sufficient therapy in patients with arginase deficiency who present with milder hyperammonemia [10].

Hemodialysis — Hemodialysis should be started as soon as possible after hospital admission of a patient
with severe hyperammonemia. 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 [11].

If these procedures are not available, continuous venovenous hemofiltration (CVVH) 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 (also known as detoxification). 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 [12]. (See "Continuous renal replacement therapy in acute
kidney injury", section on 'Definition of CRRT modality' and "Prescribing peritoneal 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. 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 and sodium benzoate. These drugs scavenge ammonia
by creating an alternate pathway to excrete nitrogen precursors [13]. Phenylacetate combines with
glutamine to form phenylacetylglutamine, and benzoate combines with glycine to form hippurate [14,15].
These conjugation products are water soluble and are excreted in the urine. Thus, adequate renal function
is essential [16]. Disposal of glutamine and glycine reduces the total nitrogen pool. Pharmacokinetics for the
biochemical conversions may vary from patient to patient. Signs of toxicity should be monitored during
treatment. Drug levels can be obtained in specialized labs, but such testing is usually not accessible in the
emergent treatment scenario.

Sodium phenylacetate and sodium benzoate — A combined preparation of sodium phenylacetate-

sodium benzoate (Ammonul) was approved by the US Food and Drug Administration (FDA) in February
2005 for parenteral delivery. 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 could be monitored in this circumstance to avoid toxicity, including death [17].

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 in the same volume as the priming dose (25 to 35 mL/kg). Maintenance infusion of Ammonul is
continued until oral sodium phenylbutyrate can be tolerated (see 'Management of infants after initial
stabilization' below). Additional intravenous fluid, 10 percent dextrose supplemented with potassium acetate
(2 to 4 mEq/100 mL), should be given to provide a total of 1 to 1.5 times daily maintenance fluid
requirements per 24 hours. The potassium will counteract the hypokalemic effects of the large sodium load
(assuming normal urine output), while the acetate base will counteract the potential acidosis due to the large
chloride load.

The effect of treatment with intravenous 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 [18]. 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 [18]. 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 therapy was 16 percent for those with neonatal-onset
UCD and 72 percent for those with late-onset UCD [19].
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) [18]. Among the 49 patients who died, 13
received higher than recommended doses of sodium phenylacetate and sodium benzoate.

Arginine — Enzyme deficiencies in the urea cycle (with the exception of arginase deficiency) prevent the
formation of arginine, thus rendering it an essential amino acid [20]. Arginine deficiency results in a catabolic
state that stimulates further mobilization of nitrogen from protein breakdown. In ornithine transcarbamylase
(OTC), argininosuccinate synthetase (ASS), and argininosuccinate lyase (ASL) deficiency, arginine also is
needed to generate urea cycle intermediates, including ornithine, citrulline, and argininosuccinic acid. When
arginine is provided, these water-soluble compounds can be formed and excreted, resulting in additional
removal of ammonia [21-23].

We administer intravenous arginine hydrochloride as part of the initial management along with dialysis and
sodium phenylacetate-sodium benzoate. In the absence of a diagnosis of the specific form of UCD, and 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, the loading dose is 4 g/m2.

The maintenance dose is started after the loading dose. In carbamoyl phosphate synthetase I (CPSI) or
OTC deficiency, or if the specific UCD is not yet identified, the 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 intravenous. 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 intravenous arginine can decrease blood pressure.

Citrulline — In OTC or CPS 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 of the
theoretical advantage of incorporating aspartate nitrogen for clearance as urea in disorders upstream of
ASS. 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 N-
acetylglutamate synthase (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
(Ammonul) 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. The dose for maintenance
treatment of chronic hyperammonemia is typically <100 mg/kg/day.
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.

Ammonia concentration is measured hourly during dialysis. After dialysis is completed and ammonia levels
have stabilized below 200 micromol/L for at least 24 hours, the frequency of measurements can be reduced
to every four hours. Testing can be reduced further 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.

Serum amino acids can be measured daily, 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. Neurologic
morbidity is directly correlated with the duration of hyperammonemia. Hence, normalization of blood
ammonia levels should be the management priority.

PROTEIN RESTRICTION

Catabolic stress should be avoided and protein intake should be restricted to minimize the nitrogen load
from protein breakdown or feeding [26]. 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
intravenous 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.

The recommended daily protein intake varies with age and ranges from 2.0 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 laboratories (ie, essential amino acid levels in the
blood, prealbumin, albumin, and hemoglobin), and clinical course.

Monitoring — 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.

MANAGEMENT OF INFANTS AFTER INITIAL STABILIZATION

In newborns who have stabilized, we begin by providing approximately 1.5 to 1.75 g/kg per day of protein as
an intravenous amino acid solution. We monitor ammonia levels at least daily and plasma amino acid levels
at least every two to three days. If this rate of protein infusion is tolerated, we discontinue the intravenous
infusion of sodium phenylacetate-sodium benzoate and administer oral sodium phenylbutyrate (Buphenyl,
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).
Sodium phenylbutyrate is converted to phenylacetate, which promotes urinary clearance of nitrogenous
waste. Citrulline (170 mg/kg per day orally) is given in ornithine transcarbamylase (OTC) and carbamoyl
phosphate synthetase I (CPSI) deficiencies, and arginine base (500 mg/kg per day orally), not the arginine
hydrochloride solution used in intravenous therapy, is given in argininosuccinate synthetase (ASS) and
argininosuccinate lyase (ASL) deficiencies. (See 'Pharmacologic therapy' above.)

Oral glycerol phenylbutyrate (Ravicti, 4.5 to 11.2 mL/m2/day divided in three equal doses) is an alternative to
oral sodium phenylbutyrate that is approved for patients two months of age and older [27-29]. 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 [30] and
the other with 15 children <6 years of age [31]). In an uncontrolled 12-month extension study, patients
showed improved measures of executive functioning compared with baseline on enrollment [30]. 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). Dosing can be guided
by fasting ammonia levels (with a target less than one-half the upper limit of normal), serum phenylacetate
levels, and urinary phenylacetylglutamine levels [32].

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 [33-35]. Thus, metabolite levels should be monitored 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 [32].
Measurement of metabolite can be performed to guide dose adjustment when there is suboptimal clinical
control, as evidenced by recurrent hyperammonemic episodes.

Enteral feeding is initiated as soon as possible. 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 intake of
protein in patients with a UCD varies with age and is determined by monitoring of nutritional biomarkers. It is
usually less than the recommended daily allowance (RDA) for age. 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.

Sodium phenylbutyrate, sodium phenylacetate, and probably also glycerol phenylbutyrate can selectively
depress branched chain amino acids (leucine, valine, and isoleucine) [36,37]. Branched chain amino acid
supplementation may be 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. Chronic administration of sodium phenylbutyrate is
associated with significant gastrointestinal side effects (eg, gastritis). Therefore, proton pump inhibitors,
such as omeprazole, are suggested. Significant gastrointestinal side effects are not expected with glycerol
phenylbutyrate, due to differences in drug metabolism. Monitoring of chronic therapy includes plasma amino
acids, measures of liver function, and nutritional markers (eg, prealbumin, albumin, plasma amino acids,
complete blood count). 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.

Laboratory 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. 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).

In a study of over 100 adult and pediatric patients who participated in the clinical trial of glycerol
phenylbutyrate, patients with baseline (fasting) glutamine values >900 micromol/L had higher baseline
ammonia levels than patients with baseline glutamine ≤900 micromol/L. Glutamine values >900 micromol/L
during the study were associated with an approximately twofold higher risk of hyperammonemic crisis.
However, glutamine lost predictive significance when concomitant ammonia was taken into account,
whereas the predictive value of baseline ammonia ≥1 upper limit of normal (ULN) was highly statistically
significant [38]. For patients with fasting ammonia concentrations <0.5 ULN, 0.5 to <1 ULN, and ≥1 ULN, the
probability of a normal average daily ammonia value was 87, 60, and 39 percent, respectively, and 10.3,
14.1, and 37 percent of these patients, respectively, experienced one or more hyperammonemic crises over
12 months [39].

Hence, optimal pharmacologic and dietary treatment should strive to 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. To optimize dosing of phenylbutyrate or glycerol phenylbutyrate, their
metabolites, phenylacetate (PAA) and phenylacetylglutamine (PAGN), can be measured in patients. 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 [40]. In a separate study of 35 patients, a PAA:PAGN ratio
between 0.6 and 1.5 was correlated with blood glutamine levels <1000 uM, a consensus target of treatment
[41].

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 parents to become familiar with the medications, formulas, and
dietary supplements. Parents 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. There is no association between
hyperammonemic episodes and immunizations in children with UCDs [42], nor is there an associated
increased risk of serious adverse events due to immunizations in children with inborn errors of metabolism
[43]. (See "Standard immunizations for children and adolescents: Overview", section on 'Routine schedule'.)

LONG-TERM MANAGEMENT

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.

For periods of increased stress, such as prior to parturition or surgery [44,45], maintenance of hydration is
indicated. For more extensive procedures or when oral intake of medications is limited, intravenous 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.

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. Prophylaxis to respiratory
syncytial virus should be considered. Parents should notify the metabolic specialist immediately if the child
becomes ill or shows early signs of hyperammonemia. Protein intake can be adjusted during acute illnesses
in conjunction with a metabolic dietician. The management of subsequent episodes of hyperammonemia is
the same as the management for the initial episode.
In specific disorders, unique pathophysiologic mechanisms may suggest adjunctive treatments. As an
example, some patients with argininosuccinic aciduria 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 [46]. However, randomized trials that confirm efficacy are necessary before
routine supplementation can be recommended. Intake of nitrite-rich foods is an acceptable conservative
recommendation.

LIVER TRANSPLANTATION

Some patients with UCD may be candidates for liver transplantation because of the high risk of mortality
and neurologic morbidity associated with UCDs [47-50]. The indications for liver transplantation are relative
[51]. 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 [52,53]. In the United States,
liver transplantation is considered for newborns with carbamoyl phosphate synthetase I (CPSI) or ornithine
transcarbamylase (OTC) deficiency, in patients who have not responded to medical therapy, and in
argininosuccinate lyase (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.

A review of 51 cases of liver transplantation for UCD (38 previously published reports and a series of 13
patients from one institution) revealed the following [54]:

● Indications for liver transplantation included OTC deficiency (22 patients), type II argininosuccinate
synthetase (ASS) deficiency (type II citrullinemia, 20 patients), type I ASS deficiency (type I
citrullinemia, 4 patients), and arginase deficiency (1 patient).

● The median age of onset of UCD was 31.5 months (range: 0 to 62 years), and the median time from
onset of UCD to liver transplantation was nine months (range: 0.5 to 202 months).

● The overall cumulative patient survival was 91 percent at 5 and 10 years. There were two hospital
mortalities, two deaths from complications of liver transplantation or remaining neurologic impairment,
two deaths unrelated to liver transplantation or UCD, and one death from biliary complications related to
graft failure.

● The overall cumulative graft survival was 89 percent at 5 and 10 years. There were three cases of graft
failure related to biliary complications (one died, one required a second liver transplantation, and one
was on a waiting list for repeat liver transplantation).

● Hyperammonemia and the need for dietary restrictions and alternative pathway medications were
completely eradicated by liver transplantation in all surviving patients. Neurologic complications
 remained in 7 of the 47 patients in whom neurologic status was evaluated (six of these received their
transplantation in early infancy). Neurologic impairments also were more likely to remain in patients
who received deceased-donor transplants than in those who received living-donor transplants (6 of 21
versus 1 of 26).

● Among the 26 living donors, 16 were known to be heterozygous for UCD, eight were not heterozygous,
and the status of two sibling donors was not known (they had a 50 percent chance of being
heterozygous). There were no descriptions of mortality or morbidity related to the use of heterozygous
donors. None of the donors showed consistent signs of hyperammonemia in the early postoperative
period or later.

In another study, early liver transplantation in patients who presented with acute hyperammonemia of limited
duration (<24 hours on average) had improved developmental outcome compared with historical trends [53].

In a 2015 review of the United Network of Organ Sharing Database, children and adults with UCDs who
underwent transplant had overall 1-, 5-, and 10-year survivals of 93, 89, and 87 percent, respectively [55].

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 and stem cell transplantation [50]. Liver
cell transplantation is much less invasive and has been performed successfully in several newborns and
older children. However, the long-term stability of the transplant is uncertain. Therefore, the majority of the
children who have survived liver cell transplantation have gone on to have orthotopic liver transplantation.
The feasibility of liver stem cell transplantation is under investigation in animal models.

Hepatocyte cell transplantation — Hepatocyte cell transplantation studies have been initiated, primarily as
a bridge to liver transplantation, although their efficacy remains to be demonstrated [56,57].

GENE THERAPY

Gene therapy was performed for ornithine transcarbamylase (OTC) deficiency in 19 patients in a phase I
trial [58-60]. This trial was halted when the 19th patient died from a severe innate immune response to the
vector [61-63]. Significant metabolic correction did not occur in the 18 surviving subjects [60]. No further
human trials have been performed, but studies in mouse models of UCDs continue.

PROGNOSIS

Mortality and morbidity are still high in UCDs [1,64,65], 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 later onset [64]. The five-year survival was 22
and 41 percent for the neonatal- and late-onset UCDs, 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 [66].
The five-year survival was 83 and 90 percent for early and late onset, respectively.

Patients often grow poorly and have neurodevelopmental problems [67]. In the earlier Japanese study, 90
percent of the neonatal survivors and 28 percent of late-onset survivors had moderate to severe
neurodevelopmental deficits [64]. 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
[66].

In another study, long-term neurologic morbidity was related to the duration of hyperammonemia and not to
peak ammonia levels [2]. 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 [68]. 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
argininosuccinic aciduria (ASA) [69,70]. Liver dysfunction can be a significant chronic complication of ASA
due to deficiency of argininosuccinate lyase (ASL) that leads to depletion of arginine. In the same vein,
neurologic morbidity does not appear to correlate with the frequency of hyperammonemia in patients with
ASA [71], and primary hypertension (formerly called "essential" hypertension) may also be associated with
deficient NO production [69]. These emerging correlations are just beginning to be understood.

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 UCD 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' above.)

● Volume repletion is necessary to minimize protein catabolism and nitrogen load and to maintain renal
function. Intravenous fluids should consist of 10 percent dextrose in water 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. We recommend use of hemodialysis if ammonia is rapidly increasing, the acute
hyperammonemia is resistant to initial drug therapy, and/or the ammonia 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 intravenous administration of a

combination preparation of sodium phenylacetate and sodium benzoate (Ammonul) followed by
maintenance with oral sodium phenylbutyrate (Buphenyl) or glycerol phenylbutyrate (Ravicti). 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. 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 must be familiar with
the medications, formulas, dietary supplements, signs of early hyperammonemia, and potential triggers
of metabolic crisis. (See 'Discharge planning' above.)

● Some patients with UCD may be candidates for liver transplantation because of the high risk of
mortality and neurologic morbidity associated with UCDs. We suggest liver transplantation for newborns
with CPSI or OTC deficiency, in patients who have not responded to medical therapy, and in ASL
deficiency associated with cirrhosis (Grade 2C). (See 'Liver transplantation' 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.

● Mortality and morbidity are high in UCDs. Patients often grow poorly and have neurodevelopmental
problems. (See 'Prognosis' above.)

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Topic 2923 Version 17.0

GRAPHICS

Urea cycle (UC)

The flow of nitrogen intermediates in the urea cycle (UC) is depicted above. The UC converts
nitrogen, derived from dietary protein intake and the breakdown of endogenous protein
(catabolism), into urea, which can be excreted from the body. The steps of this cycle, and the six
enzymes involved, are indicated in red. The dashed red arrow depicts the overflow of excess
carbamyl phosphate (CP) into pyrimidine synthesis and, hence, to orotic acid, which is excreted in
the urine. The dashed green arrow depicts the generation of nitric oxide (NO) when arginine is
converted into citrulline by nitric oxide synthase (NOS). The green cylinders denote the ornithine
and citrulline transporter (ORNT1; SLC25A15), and the blue cylinders represent the cationic
amino-acid transporter found on intestinal- and kidney-epithelial cells (SLC7A7). The pink cylinder
denotes citrin, a mitochondrial aspartate and glutamate transporter (SLC25A13).

ARG1: arginase; ASL: argininosuccinate lyase; ASS: argininosuccinate synthetase; CPS-I: carbamyl-
phosphate-synthetase-I; NAG: N-acetylglutamate; NAGS: N-acetyl-glutamate synthase; OTC: ornithine
transcarbamylase.

Courtesy of Brendan Lee, MD, PhD.

Graphic 60652 Version 2.0

Contributor Disclosures
Brendan Lee, MD, PhD Equity Ownership/Stock Options: Rainbow Genomics [Diagnostic laboratory genetic testing
(Pediatric, adult, and prenatal health DNA testing)]. Patent Holder: Acer Therapeutics (licensed) [Phenylbutyrate for
MSUD]; Genequine Therapeutics (licensed) [Helper-dependent adenovirus gene therapy for osteoarthritis].
Grant/Research/Clinical Trial Support: Sanofi/Genzyme [Osteogenesis imperfecta (Fresolumimab)]; Kirin [Wnt
modulation in osteogenesis imperfecta]. Consultant/Advisory Boards: Baylor Genetics [Diagnostic laboratory genetic
testing (Pediatric, adult, and prenatal health DNA testing)]; Acer Therapeutics [Rare disease therapeutics for Ehlers-
Danlos syndrome type IV, maple syrup urine disease, and urea cycle disorders]; Biomarin [Achondroplasia (C-naturetic
peptide analog)]. Sihoun Hahn, MD, PhD Grant/Research/Clinical Trial Support: Wilson Therapeutics AB [Wilson
disease (WTX 101-203-301 study)]; Genzyme [Pompe disease, ADVANCE (Alglucosidase alpha)].
Grant/Research/Clinical Trial Support (Spouse): Wilson Therapeutics, AB/Alexion [Wilson disease clinical trial (WTX
101-203-301 study)]; Sanofi/Genzyme [Mini-COMET study]; Sanofi/Genzyme [ISS research study, Pompe disease];
Wilson Disease Association/Yale [Wilson disease registry study]; Cystinosis Research Foundation [Newborn screening].
Consultant/Advisory Board: Alexion [Wilson disease]. Consultant/Advisory Board (Spouse): Wilson Disease Association
Medical Advisory. Elizabeth TePas, MD, MS Nothing to disclose

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