CME Review Article #7
`
`0021-972X/2002/1202-0099
`The Endocrinologist
`Copyright © 2002 by Lippincott Williams & Wilkins
`
`CHIEF EDITOR’S NOTE: This article is the 7th of 36 that will be published in 2002 for which a total of up to 36 Category 1 CME
`credits can be earned. Instructions for how credits can be earned appear after the Table of Contents.
`
`Management of Inherited Disorders
`of Ureagenesis
`
`Mendel Tuchman, M.D.* & Mark L. Batshaw, M.D.†
`
`The conversion of ammonia to urea is known to re-
`quire the function of at least nine proteins. Five of
`these are urea cycle enzymes (carbamyl phosphate
`synthetase I, ornithine transcarbamylase, argini-
`nosuccinate synthetase, argininosuccinate lyase,
`and arginase). A sixth enzyme (N-acetylglutamate
`synthase) catalyzes the formation of N-acetylgluta-
`mate, a cofactor for carbamyl phosphate synthetase
`I. The remaining three proteins are amino acid
`transporters for ornithine, aspartate/glutamate,
`and dibasic amino acids, respectively. An inherited
`deficiency in any of these proteins causes a block in
`the urea cycle and resultant hyperammonemia. Al-
`though the severity of these disorders varies, symp-
`toms, diagnostic testing, and treatments are similar.
`
`Common symptoms include episodes of vomiting,
`lethargy, and coma associated with hyperammone-
`mia. Diagnosis is based on a combination of mea-
`surement of plasma ammonia, plasma and urinary
`amino acids, urinary orotic acid, enzyme analysis,
`and molecular testing. Therapy involves a nitro-
`gen-restricted diet, supplementation of essential
`amino acids and L-citrulline/L-arginine (except for
`hyperargininemia [L-citrulline is not approved by
`the United States Food and Drug Administra-
`tion]), alternative pathway therapy with phenylbu-
`tyrate (or phenylacetate and benzoate), and, for the
`most severe cases, liver transplantation. ■
`
`The Endocrinologist 2002; 12: 99–109
`
`• Explain the best way to establish diagnosis of urea
`cycle disorders.
`• Identify and evaluate treatment options for disor-
`dered ureagenesis, emphasizing dietary management.
`• Discuss the outlook for children with complete and
`partial urea cycle defects.
`
`Introduction
`
`Urea Cycle and Related Disorders
`
`ine proteins within the liver are necessary to
`convert ammonium nitrogen, which is toxic to
`the brain, to urea, which is nontoxic (Fig. 1).
`Five enzymes comprise the urea cycle: carbamyl
`phosphate synthetase I (CPS), ornithine trans-
`carbamylase (OTC), argininosuccinate synthetase (AS),
`argininosuccinate lyase (AL), and arginase (ARG) I [1].
`Another enzyme, N-acetylglutamate synthase (NAGS),
`catalyzes the formation of N-acetylglutamate, the essential
`cofactor for CPS activity [2]. In addition, the generation of
`urea from ammonia requires at least three amino acid trans-
`porters: two located within the mitochondrial inner mem-
`
`N ❦
`
`Learning Objectives:
`
`• Describe the major clinical findings in newborn in-
`fants, older children, and adults with disorders of
`the urea cycle.
`
`*Professor and †Chief Academic Officer, Children’s Research Institute of the
`Children’s National Medical Center and the Departments of Pediatrics,
`Biochemistry, and Molecular Biology, George Washington University School
`of Medicine and Health Sciences, Washington DC.
`
`This work was supported by public health service grants DK47870 from the
`National Institute of Diabetes Digestive and Kidney Diseases, RR13297 from
`the General Clinical Research Center Program of the National Center for
`Research Resources, HD 40677 Mental Retardation and Developmental
`Disabilities Research Center from the National Institute of Child Health and
`Human Development, and a grant from Medicis Pharmaceuticals.
`
`Address correspondence to: Mendel Tuchman, M.D., Children’s National
`Medical Center, 111 Michigan Avenue NW, Washington, DC 20010.
`Phone: 202-884-2549; Fax: 202-884-6014; E-mail: mtuchman@cnmc.org.
`
`Dr. Tuchman is the recipient of a research grant from and is a consultant for
`Ucyclyd Pharma–Medicis. Dr. Batshaw is the recipient of research grants from
`the National Institute of Diabetes Digestive and Kidney Diseases, the National
`Center for Research Resources, the National Institute of Child Health and
`Human Development, and Medicis Pharmaceuticals.
`
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`IPR2017-01160
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`

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`Mangement of Inherited Disorders of Ureagenesis
`
`Figure 1. The urea cycle in a liver cell consists of six enzymes and three membrane transporters. NAGS ⫽ N-acetylglutamate synthetase; CPS ⫽ carbamyl
`phosphate synthetase I; OTC ⫽ ornithine transcarbamylase; AS ⫽ argininosuccinate synthetase; AL ⫽ argininosuccinate lyase; ARG ⫽ arginase; ORNT
`⫽ ornithine mitochondrial membrane transporter; CITR ⫽ citrin calcium-dependent mitochondrial membrane aspartate/glutamate transporter; y⫹LAT-
`1 ⫽ dibasic amino acid plasma membrane transporter.
`
`brane, the ornithine transporter [3] and the aspartate/
`glutamate transporter (called citrin or aralar II); [4] and one
`in the plasma membrane, the dibasic amino acid transporter
`(y⫹LAT-1) [5]. The two atoms of nitrogen incorporated
`into urea derive from free ammonia and aspartate. Defects
`in any one of the nine proteins involved in ureagenesis can
`cause hyperammonemia; however, the severity and the age
`at first presentation vary greatly between and even within
`the different disorders. Generally, the more proximal the
`block is, the more severe the disease. Thus, patients with
`complete CPS or OTC deficiency present almost invariably
`during the first few days of life with hyperammonemic coma,
`whereas patients with citrullinemia (AS deficiency) or
`argininosuccinic acidemia (AL deficiency) tend to present
`later, in the first month of life [6]. Arginase deficiency usu-
`ally presents later in childhood [7] as do transporters’
`defects. Defects in the ornithine transporter cause hyperor-
`nithinemia, hyperammonemia, and homocitrullinuria
`(HHH) syndrome; [8] defects in the dibasic amino acid
`transporter cause dibasic amino aciduria, also called lysin-
`uric protein intolerance (LPI) [5]. Defects in the citrin (ar-
`alar II) transporter cause citrullinemia type II [9]. Arginase
`deficiency leads to a condition termed argininemia. For
`more details on the bio- chemical and molecular basis of
`
`urea cycle disorders, please refer to “Advances in Inherited
`Urea Cycle Disorders” by Batshaw et al. [10].
`
`Clinical Findings
`
`The classic presentation of a complete defect in a urea
`cycle enzyme, other than ARG deficiency, is as a cata-
`strophic illness. Typically, the affected baby is born after an
`uncomplicated full-term pregnancy, labor, and delivery
`with normal APGAR scores. Clinical symptoms in com-
`plete CPS and OTC deficiencies develop between ages
`24 and 72 hours as poor sucking, hypotonia, vomiting,
`lethargy, and hyperventilation. This rapidly progresses to
`coma and seizures; if untreated, there is universal mortal-
`ity, and even with treatment, mortality is common [11].
`Individuals with mutations causing partial enzyme de-
`ficiencies have a spectrum of presentations, with hyperam-
`monemic episodes developing in some during infancy, in
`others during later childhood, and sometimes not until
`adulthood in others [12–14]. In infants and young chil-
`dren, recurrent episodes of vomiting, lethargy, and irri-
`tability associated with failure to thrive are common.
`In older children, there may be prolonged episodes of
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`Mangement of Inherited Disorders of Ureagenesis
`
`anorexia, ataxia, and behavioral abnormalities, including
`biting, self-injury, nocturnal restlessness, and hyperactiv-
`ity [15–19]. In adults, the symptoms may mimic psychi-
`atric or neurologic disorders and include headache,
`nausea, dysarthria, ataxia, confusion, hallucinations, and
`visual impairment [18, 20–25]. Neurologic findings may
`include increased deep tendon reflexes, papilledema, and
`decorticate or decerebrate posturing. Seizures are a late
`complication and occur after alterations in consciousness.
`Symptoms may be delayed in onset by a mild defi-
`ciency or dietary self-selection, i.e., avoidance of meats,
`fish, eggs, milk, and other high-protein foods. Individuals
`with partial defects may even remain asymptomatic
`throughout life, depending on their protein intake and ex-
`posure to precipitants of hyperammonemia (e.g., intercur-
`rent illnesses, certain drugs) [11].
`In affected individuals, acute, life-threatening, hyper-
`ammonemic episodes have been precipitated by high-
`protein meals, parenteral nutrition, viral
`infections,
`medication, trauma, surgery, pregnancy and delivery, [26]
`and exposure to insect repellent [27]. In children with
`partial defects, it is not uncommon for the initial hyperam-
`monemic episode to occur after weaning, when low-protein
`breast milk is replaced by higher-protein formula or cow’s
`milk. Treatment with valproate or haloperidol has been as-
`sociated with inducing hyperammonemic crises in patients
`with urea cycle disorders [28–31]. Valproate is believed to in-
`hibit NAGS and thus causes secondary CPS deficiency with
`resultant aggravation of hyperammonemia [32].
`Individuals with transporter defects and ARG defi-
`ciency present a somewhat different clinical picture. Al-
`though the degree of hyperammonemia and its symptoms
`are similar to partial urea cycle disorders, there are addi-
`tional clinical features that complicate the picture. In cit-
`rullinemia type II, cholestatic jaundice and pancreatitis
`have been reported [33] (pancreatitis has also been recently
`reported in OTC deficiency). In ARG deficiency and HHH
`syndrome, there is a progressive spastic paraplegia, which is
`as yet unexplained. HHH syndrome also may be associated
`with growth failure and a bleeding tendency [34]. Lysinuric
`protein intolerance is even more complex, presenting as a
`multisystem disease, which may include skeletal, pul-
`monary, renal, and hematologic abnormalities. Osteoporo-
`sis, interstitial lung disease, glomerular disease, and growth
`failure have been described in this disorder [35].
`
`Making the Diagnosis
`
`The outcome in these disorders is a function of the spe-
`cific enzymatic defect, its severity (complete or partial), age
`of onset, and the promptness of diagnosis and institution of
`
`therapy. To identify these disorders early, plasma ammonia
`levels should be measured in every acutely ill newborn.
`Plasma ammonia levels should also be measured in children
`and adults showing unexplained behavioral or neurological
`symptoms, recurrent vomiting, self-avoidance of high-
`protein foods, or atypical migraines.
`To avoid factitious increase in plasma ammonia, the
`blood should be drawn into an ice-chilled tube, and the as-
`say should be performed within 15 minutes of collection.
`Venous blood is adequate as long as the tourniquet is applied
`for only a short period of time or not at all [36]. Most hospi-
`tals now have automated analyzers that measure ammonia
`in less than 30 minutes and require less than 1 mL of blood.
`Normal plasma ammonia level is less than 35 ␮mol/L (63
`␮g/dL); it is slightly higher in premature infants. If testing is
`performed when clinical symptoms suggestive of hyperam-
`monemia are present and plasma ammonia is found to be
`normal, the cause is unlikely to be a urea cycle or related dis-
`order. However, plasma ammonia levels can be normal be-
`tween episodes in such patients. In these instances,
`increased levels of plasma glutamine, and sometimes ala-
`nine and asparagine (obtained by a quantitative amino acid
`analysis), are suggestive of a high nitrogen load [37].
`Typically, hyperammonemia resulting from urea cycle
`disorders is accompanied by a respiratory alkalosis. This
`distinguishes it from organic acidemias (e.g., propionic,
`methylmalonic, isovaleric acidemia), in which ketoacido-
`sis is usually present along with hyperammonemia (Fig. 2).
`Although serum blood urea nitrogen concentration is
`lower than normal in urea cycle disorders (as a result of re-
`duced ureagenesis), it can be subnormal in any patients
`with a decreased protein intake. Liver function test results
`are usually within normal limits in urea cycle disorders
`when the patient is clinically stable but could be tran-
`siently abnormal during hyperammonemic episodes.
`Once hyperammonemia has been detected, the differ-
`ential diagnosis requires the measurements of plasma and
`urinary amino acids, urinary organic acids, and orotic acid
`and plasma lactate (Fig. 3). Urinary organic acids are largely
`unremarkable in urea cycle and related disorders (except for
`orotic acid, which could be detected when massively in-
`creased), whereas they are abnormal in organic acidemias,
`congenital lactic acidoses, and fatty acid oxidation defects.
`Measurement of lactic acid and acylcarnitines can help dis-
`tinguish between these three groups of disorders.
`In differentiating among the primary urea cycle disor-
`ders, the citrulline level helps identify proximal versus dis-
`tal defects. Citrulline is the product of CPS and OTC and
`is a substrate for AS and AL. As a result, plasma citrulline
`is absent or present in only trace amounts in complete-
`onset CPS and OTC deficiencies, but it may be low or
`
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`Mangement of Inherited Disorders of Ureagenesis
`
`Figure 2. Algorithm for the differential diagnosis of inherited hyperammonemia.
`
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`Mangement of Inherited Disorders of Ureagenesis
`
`Figure 3. The urea cycle and drug therapy for urea cycle disorders. This therapy includes compounds that use alternative pathways to excrete waste ni-
`trogen (phenylbutyrate, phenylacetate, benzoate, and arginine) and supplementation of essential components (arginine, citrulline, and carbamyl glu-
`tamate).
`
`even normal in patients with milder, late-onset disorders.
`Citrulline is low or normal in NAGS deficiency. In con-
`trast, AS deficiency (citrullinemia) is marked by up to a
`100-fold increase in plasma citrulline, whereas citrulline-
`mia type II and argininosuccinic acidemia (AL deficiency)
`show an approximately 10-fold increase.
`Argininosuccinate lyase deficiency is distinguished by
`the presence of argininosuccinic acid (ASA) in blood and
`urine. It should be noted that the ASA chromatographic
`peak co-elutes with leucine or isoleucine, resulting in an
`apparent increase in one of these amino acids. The anhy-
`drides of ASA elute later (approximately at the times of
`homocystine and ␥-aminobutyric acid), and this should
`permit the correct identification of ASA.
`To distinguish CPS from OTC deficiency, urinary
`orotic acid is measured; although low in CPS and NAGS
`deficiency, it is markedly increased in OTC and ARG de-
`ficiency. Urinary orotate excretion also can be mildly in-
`creased in AS and AL deficiencies and in the transport
`defects. Plasma arginine is decreased in all primary urea cy-
`cle disorders, except in argininemia, in which it is approx-
`imately increased 10-fold to 20-fold.
`In the transport defects, HHH syndrome is distin-
`guished by increases in plasma ornithine (200–1000
`␮mol/L) and urinary homocitrulline levels while plasma ly-
`sine is low. Markers for lysinuric protein intolerance include
`massively increased urinary excretion of lysine and moder-
`
`ate increases in arginine and ornithine excretion associated
`with low plasma lysine, arginine, and ornithine. As noted,
`in citrullinemia type II, plasma and urinary citrulline levels
`are increased, although less markedly than in AS deficiency.
`Whereas AS, AL, and ARG deficiencies and the
`transport defects can be distinguished by their unique
`plasma and/or urinary amino acid profiles, a definitive di-
`agnosis of CPS, OTC, and NAGS deficiencies depends on
`enzyme determination on a liver biopsy or molecular diag-
`nosis on DNA (in OTC and CPS deficiency). In OTC de-
`ficiency, 75% to 80% of patients have been found to have
`an identifiable mutation by DNA studies [38].
`
`Treatment
`
`Severe hyperammonemia (⬎250 ␮mol/L) is almost
`always associated with altered consciousness, and levels
`more than 500 ␮mol/L cause swelling of astrocytes with re-
`sultant cytotoxic brain edema [39]. This life-threatening
`condition is best treated with hemodialysis (or, when this
`is not available, with hemofiltration) to remove the of-
`fending toxin as rapidly as possible. Otherwise, vascular
`compromise and/or brain herniation will ensue. During a
`hyperammonemic crisis, catabolism becomes more pro-
`nounced, ammonia production increases markedly, and
`the condition may quickly become irreversible. In less se-
`
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`Mangement of Inherited Disorders of Ureagenesis
`
`vere episode of hyperammonemia (100–250 ␮mol/L), the
`patient usually responds to intravenous alternative path-
`way therapy (see later in this article). This stimulates the
`elimination of waste nitrogen by biochemical reactions,
`which do not require urea cycle enzymes.
`Long-term therapy involves restriction of dietary ni-
`trogen intake, amino acid supplements, and stimulation of
`alternative pathways of waste nitrogen excretion. Ortho-
`topic liver transplantation has been performed to replace
`deficient enzyme activity in patients with a number of urea
`cycle and related conditions [40, 41]. For a detailed discus-
`sion of treatment, see the “Proceedings of the Consensus
`Conference for the Management of Patients With Urea
`Cycle Disorders” [42].
`
`Dietary Management
`
`In neonates and young infants, dietary management in-
`volves nitrogen restriction combined with sufficient caloric
`intake to minimize amino acid degradation. This is accom-
`plished by using a low-protein infant formula supplemented
`with essential amino acids and a nonprotein-containing
`caloric supplement [43]. In toddlers, the formula is replaced
`by low-protein food (Table 1). In school-aged children, ni-
`trogen restriction can often be accomplished using a pro-
`tein-restricted diet, similar to that provided to patients with
`
`chronic renal failure. In ARG deficiency, the low-protein
`diet should also be low in arginine.
`In calculating dietary requirements, it is recommended
`that the minimum daily protein allowance required for
`growth be used [44]. Clinical indications of adequate pro-
`tein intake include normal linear growth velocity and the
`absence of signs of undernutrition (e.g., rashes, abnormal or
`fragile hair and fingernails). Laboratory indicators of re-
`stricted yet adequate protein intake include normal serum
`proteins and preprandial plasma amino acids levels at the
`low range of normal. Special attention should be given to
`plasma levels of glutamine, branched-chain amino acids,
`and arginine. Glutamine is a scavenger of ammonia, and
`when increased indicates nitrogen overload. The goal for
`therapy is to maintain plasma glutamine levels within the
`normal range (⬍800 ␮mol/L) or at least less than 1,000
`␮mol/L. The branched-chain amino acids, although im-
`portant in maintaining anabolic conditions, can produce
`ammonia when administered in excess. Thus, they should
`be maintained in the low normal range.
`
`Arginine, Citrulline, and
`Carbamylglutamate Supplementation
`
`Because arginine is the product of the first four en-
`zymes in the urea cycle (CPS, OTC, AS, AL), it becomes
`
`Table 1
`Long-Term Treatment of Urea Cycle Disorders (g/kg per day unless otherwise specified)
`
`Disorder
`
`Neonatal onset
`CPS or OTC
`deficiency
`Late onset CPS or
`OTC deficiency
`Citrullinemia
`
`Argininosuccinic
`acidemia
`Argininemia
`
`Protein
`Intake1
`
`1.4–1.9
`
`1.2–1.4
`
`1.2–1.9
`
`1.2–1.9
`
`0.5–1.4
`
`NAGS deficiency3
`
`1.2–1.9
`
`LPI4
`
`HHH syndrome5
`
`1.0–1.5
`
`1.0–1.5
`
`L-Citrulline
`
`L-Arginine Free Base
`
`Sodium Phenylbutyrate2
`
`0.17 or 3.8 g/M2
`per day
`
`0.17 or 3.8 g/M2
`per day
`—
`
`—
`
`—
`
`—
`
`0.17 or 3.8 g/M2
`per day
`0.17 or 3.8 g/M2
`per day7
`
`—
`
`—
`
`0.40–0.70 or 8.8–
`15.4 g/M2 per day
`0.40–0.70 or 8.8–
`15.4 g/M2 per day
`
`—
`
`0.17 or 3.8 g/M2
`per day
`0.17 or 3.8 g/M2
`per day
`—
`
`0.45–0.60 if ⬍20 kg; 9.9–13.0 g/M2 per
`day in larger patients
`
`0.45–0.60 if ⬍20 kg; 9.9–13.0 g/M2
`per day in larger patients
`0.45–0.60 if ⬍20 kg; 9.9–13.0 g/M2
`per day in larger patients
`Usually not required
`
`0.45–0.60 if ⬍20 kg; 9.9–13.0 g/M2
`per day in larger patients
`0.45–0.60 if ⬍20 kg; 9.9–13.0 g/M2
`per day in larger patients
`0.45–0.60 if ⬍20 kg; 9.9–13.0 g/M2
`per day in larger patients
`0.45–0.60 if ⬍20 kg; 9.9–13.0 g/M2
`per day in larger patients
`
`1Caloric requirement may be completed using a protein-free formula. In general, the minimum daily protein intake for growth was used: for 1–4 mo,
`1.6–1.9 g/kg per day; for 4–12 mo, 1.7 g/kg per day; for 1–3 y, 1.4 g/kg per day. Daily protein intake may include an essential amino acid formula.
`2If intolerant of phenylbutyrate, Ucephan (Na-benzoate ⫹ Na-phenylacetate) can be administered orally at a dose of 0.25 g/kg per day each.
`3Carbamylglutamate may also be administered at a dose of 0.32–0.65 g/kg per day.
`4 L-citrulline or L-arginine should be used. Ornithine or lysine can also be administered at a dose of 0.1–0.25 g/kg per day.
`5Ornithine 0.18 g/kg per day can be substituted for citrulline.
`
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`Mangement of Inherited Disorders of Ureagenesis
`
`an essential amino acid in these patients and thus needs to
`be supplemented to maintain a normal rate of protein syn-
`thesis. Arginine also enhances the production of N-acetyl-
`glutamate by NAGS, and its deficiency may have a
`deleterious effect on CPS activity. Arginine deficiency can
`result in an erythematous scaling and weeping rash, hair
`loss, as well as aggravation of hyperammonemia [45].
`In CPS and OTC deficiencies, arginine supplementa-
`tion can be replaced by citrulline, which incorporates an ad-
`ditional nitrogen atom on conversion to arginine. The
`recommended dose for citrulline is 170 mg/kg per day (3.8
`g/M2 per day). In HHH syndrome and in lysinuric protein
`intolerance, a similar dose of citrulline is used to stimulate
`ornithine and arginine production and transport [46, 47]. In
`NAGS deficiency, arginine supplementation is combined
`with carbamylglutamate (380 mg/kg per day), a stable func-
`tional analog of N-acetylglutamate [48]. This therapy has
`resulted in an increase of blood urea nitrogen, a decrease in
`ammonia levels, and clinical improvement. It has recently
`been suggested that carbamylglutamate can also stimulate
`residual CPS activity in partial CPS deficiency [49].
`In citrullinemia and argininosuccinic acidemia, argi-
`nine is administered not only to replace its deficient pro-
`duction but also to stimulate waste nitrogen excretion.
`Here, large doses of arginine (400–600 mg/kg per day,
`8.8–15.4 g/M2 per day) are used to “prime” the urea cycle
`and enhance the production and urinary excretion of cit-
`rulline and ASA, respectively [50, 51].
`Argininosuccinic acid contains both waste nitrogen
`atoms destined for excretion as urea. Furthermore, it has a
`renal clearance equal to the glomerular filtration rate.
`Thus, provided it is continuously synthesized and ex-
`creted, ASA could serve as an effective substitute for urea
`as a waste nitrogen product in argininosuccinic acidemia.
`There is, however, the possibility that increased produc-
`tion of ASA or its derivatives might be responsible for the
`liver disease seen in many patients with this disorder.
`Therefore, an alternative approach can be considered,
`which combines a lower dose of arginine with phenylbu-
`tyrate (see later).
`Like ASA, citrulline can be a vehicle for waste nitro-
`gen excretion in citrullinemia. Although it contains only
`a single waste nitrogen atom and is excreted less efficiently
`than ASA, the high plasma concentration allows signifi-
`cant “spillover” of citrulline into the urine and thus elim-
`ination of nitrogen. Phenylbutyrate is typically added to
`the arginine supplementation in treating citrullinemia.
`Patients with argininosuccinic acidemia who receive
`arginine therapy have low plasma aspartate levels because
`of incorporation of aspartate into ASA without the normal
`production of fumarate (Fig. 1). Whether this biochemical
`
`aberration has pathological significance is unknown, but
`some authors have advocated supplementing these patients
`with citrate, which can be converted to oxaloacetate in the
`Krebs cycle and then to aspartate by transamination [52].
`
`Alternative Pathway Therapy
`
`Treatment aimed at activating other pathways of ni-
`trogen excretion varies with the site of the enzymatic
`block. As noted previously, in citrullinemia and arginino-
`succinic acidemia, arginine serves this purpose. In other
`urea cycle disorders, sodium phenylbutyrate (Buphenyl;
`Ucycld Pharma, Phoenix, AZ) is used. Phenylbutyrate is
`metabolized to phenylacetate by ␤-oxidation, which is
`then enzymatically ligated to glutamine to form phenyl-
`acetylglutamine (Fig. 3). This compound contains two
`waste nitrogen molecules (from glutamine) and is readily
`excreted in the urine [53]. The use of phenylbutyrate avoids
`the repugnant odor of phenylacetate while having the same
`therapeutic effect. More than 40% of total waste nitrogen
`can be excreted as phenylacetylglutamine using this ap-
`proach.
`Commonly used therapeutic doses of phenylbutyrate
`are 450 to 600 mg/kg per day for children weighing less
`than 20 kg and 9.9 to 13 g/M2 per day in larger patients.
`The dose can, however, be adjusted downward depending
`on the severity of the disorder and the level of plasma glu-
`tamine. The daily medication is divided into three to four
`doses and is generally administered with each meal. The
`most common adverse effect of sodium phenylbutyrate is
`gastric irritation leading to epigastric pain, nausea, and
`vomiting. Blood levels of the medication should be
`checked after starting phenylbutyrate, after a change in
`dosage, with loss of metabolic control, and with symptoms
`suggestive of toxicity. Most patients using these doses have
`blood phenylbutyrate peak levels (1.5 hours after the dose)
`of approximately 220 to 550 ␮mol/L and phenylacetate
`levels between 310 and 470 ␮mol/L. Trough level of
`phenylbutyrate is usually less than 25 and less than 170
`␮mol/L for phenylacetate [54].
`When intravenous treatment is needed for acute hy-
`perammonemic episodes, a combination of sodium ben-
`zoate, which is not approved by the Food and Drug
`Administration, and sodium phenylacetate, which is also
`not approved by the United States Food and Drug Admin-
`istration, (Ammonul; Ucyclyd Pharma) is used [55]. This is
`because phenylbutyrate is not available in an injectable
`form. Benzoate is conjugated with glycine to form hippuric
`acid (benzoylglycine), which is excreted in the urine (Fig.
`3). For every molecule of conjugated benzoate, one atom of
`nitrogen (from glycine) is eliminated. As noted previously,
`
`The Endocrinologist
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`Mangement of Inherited Disorders of Ureagenesis
`
`phenylacetate is conjugated with glutamine, eliminating
`two atoms of nitrogen for each conjugated molecule.
`
`Liver Transplantation
`
`A number of patients with various urea cycle and re-
`lated disorders, most commonly CPS and OTC deficiencies,
`have undergone orthotopic liver transplantations [40]. This
`procedure has corrected the hyperammonemia and permit-
`ted a normal protein intake. Liver transplantation does not,
`however, correct the citrulline (and thus arginine) defi-
`ciency in CPS-deficient and OTC-deficient patients [56].
`Therefore, arginine may need to be supplemented after
`transplantation, especially during periods of decreased pro-
`tein intake. The effectiveness of liver transplantation has
`been affected by limited availability of organs, significant
`morbidity, and cost. Despite these concerns, liver transplan-
`tation should be seriously considered for patients with
`neonatal presentation of CPS and OTC deficiencies or for
`other poorly controlled urea cycle and related disorders.
`
`Anticipatory Treatment of Intercurrent
`Hyperammonemia
`
`Anticipation and early treatment of intercurrent hyper-
`ammonemic episodes are essential, because intervention is
`most effective at lower ammonium levels, and an adverse
`neurological outcome appears to be a function of the magni-
`tude and duration of hyperammonemia. After living with
`their child’s illness for some time, parents become reliable
`observers of early signs of hyperammonemia. They recog-
`nize subtle changes in their child’s behavior or eating pattern
`that suggest a metabolic decompensation. Thus, physicians
`should pay close attention to parental observations. A rea-
`sonable policy is to measure plasma ammonium levels when
`the family requests this to be performed. In addition, symp-
`tomatic hyperammonemia has been found to be preceded,
`often over the course of weeks, by increases in plasma gluta-
`mine levels (more than 1,000 ␮mol/L). Therefore, periodic
`measurement of plasma amino acids (including glutamine)
`may permit adjustment of therapy before clinical symptoms
`appear [57]. When only asymptomatic biochemical abnor-
`malities are detected, the patient usually responds to de-
`creasing nitrogen intake and/or to increasing the doses of
`citrulline or arginine and phenylbutyrate if feasible.
`
`Therapy for Symptomatic Hyperammonemia
`
`If vomiting and lethargy appear, plasma ammonia levels
`are usually more than 150 ␮mol/L, and aggressive treatment
`is required. The child should be hospitalized with complete
`
`elimination of protein for 24 hours and intravenous treat-
`ment with sodium benzoate, sodium phenylacetate, and L-
`arginine-HCl (R-Gene 10; Upjohn, Kalamazoo, MI;
`L-arginine-HCl is not approved by the United States Food
`and Drug Administration for this indication). A priming
`dose of sodium benzoate plus sodium phenylacetate (250
`mg/kg or 5.5 g/M2 of each) is administered over the course of
`90 minutes in 25 to 35 mL/kg (400–600 mL/M2) of 10% glu-
`cose and then the same dose should be administered over the
`course of the next 24 hours as a constant infusion. These
`drugs (250 mg/kg per 24 hours) are then continued until oral
`phenylbutyrate therapy can be restarted, usually after ammo-
`nia levels have decreased to less than 100 ␮mol/L. Vomiting
`often occurs during the priming dose of benzoate and phenyl-
`acetate; ondansetron HCl (Zofran; GlaxoSmithKline, Pitts-
`burgh, PA), a potent antiemetic, can be administered
`intravenously (0.15 mg/kg) 30 minutes before the infusion.
`For CPS and OTC deficiencies, intravenous arginine-
`HCl 10% 200 mg/kg (2 mL/kg) is administered over the
`course of 90 minutes and then the same dose is adminis-
`tered over the course of the next 24 hours. For citrulline-
`mia and argininosuccinic acidemia, the priming dose of
`arginine-HCl 10% is 6 mL/kg, and then the same dose is
`administered over the course of the next 24 hours.
`Nonprotein calories should be provided as glucose
`(8–10 mg/kg per minute in newborns and lower rates in
`older infants and children). Intravenous lipids should also
`be added to maintain a caloric intake of 80 kcal/kg per day
`and promote anabolism. Vitamins and trace elements
`should be provided in the intravenous solution.
`It has been suggested that carnitine supplements (50–
`100 mg/kg per day) may be helpful as adjunctive therapy
`during hyperammonemic crises [58]. Neomycin and lactu-
`lose have also been used as a means of decreasing nitrogen
`production by intestinal bacteria during hyperammonemia
`[59]. However, their role in the acute treatment of urea cy-
`cle disorders is unclear.
`Careful consideration should be given to electrolyte
`balance. Because 1 g sodium benzoate and sodium phenyl-
`acetate contains 160 mg and 146 mg sodium, respectively,
`additional sodium should not be administered in the in-
`travenous solution because hypernatremia can develop.
`Sufficient amounts of chloride are usually provided by the
`arginine-HCl; however, low concentrations of NaCl (e.g.,
`1⁄5 normal saline) can be added to the glucose solution to
`replace chloride. Hypokalemia can result from urinary
`potassium loses enhanced by hippurate and phenylacetyl-
`glutamine excretion as well as by driving potassium into
`the cells as a result of the high glucose administration.
`Potassium should be added to the maintenance intra-
`venous fluid but not to the priming solution.
`
`106
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`Mangement of Inherited Disorders of Ureagenesis
`
`Toxicity and Overdosing
`
`Life-threatening toxicity from intravenous alterna-
`tive pathway therapy is rare, but overdoses of benzoate and
`phenylacetate have led to symptoms that mimic salicylate
`poisoning, including ketoacidosis, encephalopathy, and
`hyperventilation [60]. This can result in hypernatremia,
`hyperosmolarity, and fatal cardiopulmonary collapse. Sev-
`eral deaths have been reported from overdosing; thus, the
`dosage should be checked carefully for this infrequently
`used medication. Arginine-HCl can cause a metabolic aci-
`dosis, which can be treated with sodium bicarbonate. Be-
`cause extravasation can cause severe tissue necrosis caused
`by the HCl, L-arginine-HCl, which is not approved by the
`Unite