Management Of Urea Cycle Disorders Research Articles

Monitoring the treatment of urea cycle disorders using phenylbutyrate metabolite analyses: Still many lessons to learn

Medications that elicit an alternate pathway for nitrogen excretion such as oral sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB) and intravenous sodium phenylacetate (NaPAA) are important for the management of urea cycle disorders (UCDs). Plasma concentrations of their primary metabolite, phenylacetate (PAA), as well as the ratio of PAA to phenylacetylglutamine (PAGN) are useful for guiding dosing and detecting toxicity. However, the frequency of toxic elevations of metabolites and associated clinical covariates is relatively unknown. A retrospective analysis was conducted on 1255 plasma phenylbutyrate metabolite measurements from 387 individuals. An additional analysis was also conducted on a subset of 68 individuals in whom detailed clinical information was available. In the course of these analyses, abnormally elevated plasma PAA and PAA:PAGN were identified in 39 individuals (4.15% of samples) and 42 individuals (4.30% of samples), respectively. Abnormally elevated PAA and PAA:PAGN values were more likely to occur in younger individuals and associate positively with dose of NAPBA and negatively with plasma glutamine and glycine levels. These results demonstrate that during routine clinical management, the majority of patients have PAA levels that are deemed safe. As age is negatively associated with PAA levels however, children undergoing treatment with NaPBA may need close monitoring of their phenylbutyrate metabolite levels.

Study of the inclusion complexes formed between 4-phenylbutyrate and α-, β- and γ-cyclodextrin in solution and evaluation on their taste-masking properties.

4-Phenylbutyrate (PB), which is used in the management of urea cycle disorders, has an unpleasant taste leading to poor patient compliance. Existing PB formulations though helpful, have some limitations in their use. This study reports on attempts to mask this unpleasant taste by complexing PB with cyclodextrins (CDs) to improve patient compliance. α, β and γCD were used as CDs. Phase solubility studies, circular dichroism, 1H-NMR spectroscopy, including ROESY, and molecular modelling were used to investigate and characterize the PB-CD interactions in solution. The taste-masking effect of the CDs was evaluated using in vitro taste sensor measurements. PB interacts with α, β and γCD in solution to form 1:1, 1:1 and 1:2 CD: PB inclusion complexes, respectively, with stability constants in the order αCD > βCD > γCD. Taste evaluation revealed that the CDs significantly mask the taste of PB through the formation of the inclusion complexes. Notably, αCD masked the bitter taste of PB to 30% of the initial taste at a 1:1 molar ratio. αCD significantly masks the unpleasant taste of PB in solution and can be used to formulate PB to address the limitations of existing formulations and improve patient compliance and quality of life.

Guidelines for diagnosis, treatment and management of urea cycle disorders in China

尿素循环障碍是一组致残率高、致死率高的遗传代谢性疾病。为提高我国相关领域医生对该病的诊疗管理水平，特制订“中国尿素循环障碍诊断治疗和管理指南”，基于当前可获得的临床证据，针对尿素循环障碍诊断、治疗和管理相关12个临床问题提供了对应参考意见。.

Targeted Breast Milk Modification

Background: The management of urea cycle disorders (UCDs) needs use of nitrogen scavenger drugs and protein restricted special formulas. The latter is not easily accessible and expensive. Continued breastfeeding is poorly tolerated by most babies. In these circumstances, targeted breast milk modification can be lifesaving by reducing ammonia and preventing a catabolic state. Clinical Description: A term baby born by normal delivery was discharged at 48 h after successfully initiating breastfeeding. He developed lethargy, poor feeding, and seizures on the 4th day. Vitals were stable. Sepsis, hypoglycemia, hypoxic-ischemic encephalopathy, dyselectrolytemia, hepatic/renal derangement, structural brain anomalies, cerebral edema, and hemorrhage were ruled out. A UCD was suspected due to hyperammonemia without acidosis. Citrullinemia was established by elevated citrulline and no orotic acid. Management: Breastfeeding was stopped, nitrogen scavenger drugs started, and peritoneal dialysis performed. As specialized milk formula was unavailable, we started diluted breast milk mixed with corn starch and coconut oil to achieve protein restriction and provide appropriate carbohydrates, lipids, and energy. Dilution was gradually decreased. There was gradual improvement in sensorium with normalization of ammonia. The baby was well till 8 weeks but developed symptomatic hyperammonemia due to noncompliance with therapy. Conclusion: Targeted modification of breast milk may be the only viable option for feeding infants with UCD in extraordinary circumstances. However, its short- and long-term consequences need to be researched thoroughly.

Primary hyperammonaemia: Current diagnostic and therapeutic strategies.

Primary hyperammonaemia is a term to describe an elevation of ammonia in blood or plasma due to a defect within the urea cycle, which is the pathway responsible for ammonia detoxification and arginine biosynthesis. Urea cycle disorders (UCDs) are rare diseases caused by genetic defects affecting any of the six enzymes or two transporters that are directly involved in the urea cycle function.The clinical situation is variable and largely depends on the time of onset. Newborns who are often affected by hyper-ammonaemic encephalopathy carry a potential risk of severe brain damage, which may lead to death. Outside the neonatal period, symptoms are very unspecific but most often neurological (with wide variability), psychiatric and/or gastrointestinal. Early identification of patients is extremely important to start effective treatment modalities immediately. The acute management includes detoxification of ammonia, which often requires extracorporeal means such as haemodialysis, and the use of intravenous drugs that work as nitrogen scavengers. Long-term management of patients with UCDs consists of a low-protein diet, which needs to be balanced and supplemented to avoid deficiencies of essential amino acids, trace elements or vitamins and the use of nitrogen scavengers.The reader will find here a brief overview describing the most relevant aspects of the clinical management of UCDs in an attempt to raise awareness for this important group of rare diseases.

Untargeted metabolomic profiling reveals multiple pathway perturbations and new clinical biomarkers in urea cycle disorders

PurposeUntargeted metabolomic analysis is increasingly being used in the screening and management of individuals with inborn errors of metabolism (IEM). We aimed to test whether untargeted metabolomic analysis in plasma might be useful for monitoring the disease course and management of urea cycle disorders (UCDs). MethodsUntargeted mass spectrometry–based metabolomic analysis was used to generate z-scores for more than 900 metabolites in plasma from 48 individuals with various UCDs. Pathway analysis was used to identify common pathways that were perturbed in each UCD. ResultsOur metabolomic analysis in plasma identified multiple potentially neurotoxic metabolites of arginine in arginase deficiency and, thus, may have utility in monitoring the efficacy of treatment in arginase deficiency. In addition, we were also able to detect multiple biochemical perturbations in all UCDs that likely reflect clinical management, including metabolite alterations secondary to dietary and medication management. ConclusionIn addition to utility in screening for IEM, our results suggest that untargeted metabolomic analysis in plasma may be beneficial for monitoring efficacy of clinical management and off-target effects of medications in UCDs and potentially other IEM.

Acute Illness Protocol for Urea Cycle Disorders.

Inborn errors of metabolism (IEMs) are genetic disorders that disrupt enzyme activity, cellular transport, or energy production. They are individually rare but collectively have an incidence of 1:1000. Most patients with IEMs are followed up by a physician with expertise in biochemical genetics (metabolism), but may present outside this setting. Because IEMs can present acutely with life-threatening crises that require specific interventions, it is critical for the emergency physician, internist, and critical care physician as well as the biochemical geneticist to have information on the initial assessment and management of patients with these disorders. Appropriate early care can be lifesaving. This protocol is not designed to replace the expert consultation of a biochemical geneticist, but rather to improve early care and increase the level of comfort of the acute care physician with initial management of urea cycle disorders until specialty consultation is obtained.

Safety and efficacy of glycerol phenylbutyrate for management of urea cycle disorders in patients aged 2months to 2years.

Glycerol phenylbutyrate (GPB) is approved in the US for the management of patients 2months of age and older with urea cycle disorders (UCDs) that cannot be managed with protein restriction and/or amino acid supplementation alone. Limited data exist on the use of nitrogen conjugation agents in very young patients. Seventeen patients (15 previously on other nitrogen scavengers) with all types of UCDs aged 2months to 2years were switched to, or started, GPB. Retrospective data up to 12months pre-switch and prospective data during initiation of therapy were used as baseline measures. The primary efficacy endpoint of the integrated analysis was the successful transition to GPB with controlled ammonia (<100μmol/L and no clinical symptoms). Secondary endpoints included glutamine and levels of other amino acids. Safety endpoints included adverse events, hyperammonemic crises (HACs), and growth and development. 82% and 53% of patients completed 3 and 6months of therapy, respectively (mean 8.85months, range 6days-18.4months). Patients transitioned to GPB maintained excellent control of ammonia and glutamine levels. There were 36 HACs in 11 patients before GPB and 11 in 7 patients while on GPB, with a reduction from 2.98 to 0.88 episodes per year. Adverse events occurring in at least 10% of patients while on GPB were neutropenia, vomiting, diarrhea, pyrexia, hypophagia, cough, nasal congestion, rhinorrhea, rash/papule. GPB was safe and effective in UCD patients aged 2months to 2years. GPB use was associated with good short- and long-term control of ammonia and glutamine levels, and the annualized frequency of hyperammonemic crises was lower during the study than before the study. There was no evidence for any previously unknown toxicity of GPB.

Polysaccharide-based aerogel microspheres for oral drug delivery.

Polysaccharide-based aerogels in the form of microspheres were investigated as carriers of poorly water soluble drugs for oral administration. These bio-based carriers may combine the biocompatibility of polysaccharides and the enhanced drug loading capacity of dry aerogels. Aerogel microspheres from starch, pectin and alginate were loaded with ketoprofen (anti-inflammatory drug) and benzoic acid (used in the management of urea cycle disorders) via supercritical CO2-assisted adsorption. Amount of drug loaded depended on the aerogel matrix structure and composition and reached values up to 1.0×10(-3) and 1.7×10(-3) g/m(2) for ketoprofen and benzoic acid in starch microspheres. After impregnation, drugs were in the amorphous state in the aerogel microspheres. Release behavior was evaluated in different pH media (pH 1.2 and 6.8). Controlled drug release from pectin and alginate aerogel microspheres fitted Gallagher-Corrigan release model (R(2)>0.99 in both cases), with different relative contribution of erosion and diffusion mechanisms depending on the matrix composition. Release from starch aerogel microspheres was driven by dissolution, fitting the first-order kinetics due to the rigid starch aerogel structure, and showed different release rate constant (k1) depending on the drug (0.075 and 0.160 min(-1) for ketoprofen and benzoic acid, respectively). Overall, the results point out the possibilities of tuning drug loading and release by carefully choosing the polysaccharide used to prepare the aerogels.

Orphan drugs in development for urea cycle disorders: current perspectives

Orphan drugs in development for urea cycle disorders: current perspectives Johannes H&auml;berle,1 Shawn E McCandless2 1Division of Metabolism and Children&#39;s Research Center, University Children&#39;s Hospital Zurich, Zurich, Switzerland; 2Center for Human Genetics, University Hospitals Case Medical Center, and Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA Abstract: The urea cycle disorders are caused by deficiency of one of the six hepatic enzymes or two transporters involved in detoxification of ammonia. The resulting hyperammonemia causes severe brain injury unless aggressive steps are taken to reduce the accumulation of ammonia, which is thought to be the most toxic metabolite. This review describes the current state of chronic management of urea cycle disorders, focusing on new and emerging therapies. Management strategies include the mainstay of treatment, namely dietary protein restriction and supplementation with l-arginine or l-citrulline. Several currently approved medications utilize and enhance alternative pathways of waste nitrogen excretion (sodium benzoate, sodium phenylacetate, sodium phenylbutyrate in several formulations, and glycerol phenylbutyrate), working through conjugation of the drug to either glycine (in the case of benzoate) or glutamine, the products of which are excreted in the urine. Carglumic acid activates the first committed step of conversion of ammonia to urea, carbamoylphosphate synthetase, and thus effectively treats defective synthesis of the endogenous activator, N-acetylglutamate, whether due to genetic defects or biochemical inhibition of the N-acetylglutamate synthase enzyme. Approaches to neuroprotection during episodes of hyperammonemia are discussed, including the use of controlled hypothermia (brain cooling), as well as proposed, but as yet untested, pharmacologic therapies. Finally, cell-based therapies, including liver transplantation, infusion of fresh or cryopreserved hepatocytes, use of stem cells, and new approaches to gene therapy, are reviewed. Keywords: urea cycle disorders, inherited hyperammonemias, orphan drugs, phenylbutyrate, N-carbamyl-l-glutamate

Evaluation of Implementation, Adaptation and Use of the Recently Proposed Urea Cycle Disorders Guidelines.

Implementation of guidelines and assessment of their adaptation is not an extensively investigated process in the field of rare diseases. However, whether targeted recipients are reached and willing and able to follow the recommendations has significant impact on the efficacy of guidelines. In 2012, a guideline for the management of urea cycle disorders (UCDs) has been published. We evaluate the efficacy of implementation, adaptation, and use of the UCD guidelines by applying different strategies. (i) Download statistics from online sources were recorded. (ii) Facilities relevant for the implementation of the guidelines were assessed in pediatric units in Germany and Austria. (iii) The guidelines were evaluated by targeted recipients using the AGREE instrument. (iv) A regional networking-based implementation process was evaluated. (i) Download statistics revealed high access with an increase in downloads over time. (ii) In 18% of hospitals ammonia testing was not available 24/7, and emergency drugs were often not available. (iii) Recipient criticism expressed in the AGREE instrument focused on incomplete inclusion of patients' perspectives. (iv) The implementation process improved the availability of ammonia measurements and access to emergency medication, patient care processes, and cooperation between nonspecialists and specialists. Interest in the UCD guidelines is high and sustained, but more precise targeting of the guidelines is advisable. Surprisingly, many hospitals do not possess all facilities necessary to apply the guidelines. Regional network and awareness campaigns result in the improvement of both facilities and knowledge.

Dietary management of urea cycle disorders: European practice

BackgroundThere is no published data comparing dietary management of urea cycle disorders (UCD) in different countries. MethodsCross-sectional data from 41 European Inherited Metabolic Disorder (IMD) centres (17 UK, 6 France, 5 Germany, 4 Belgium, 4 Portugal, 2 Netherlands, 1 Denmark, 1 Italy, 1 Sweden) was collected by questionnaire describing management of patients with UCD on prescribed protein restricted diets. ResultsData for 464 patients: N-acetylglutamate synthase (NAGS) deficiency, n=10; carbamoyl phosphate synthetase (CPS1) deficiency, n=29; ornithine transcarbamoylase (OTC) deficiency, n=214; citrullinaemia, n=108; argininosuccinic aciduria (ASA), n=80; arginase deficiency, n=23 was reported. The majority of patients (70%; n=327) were aged 0–16y and 30% (n=137) >16y. Prescribed median protein intake/kg body weight decreased with age with little variation between disorders. The UK tended to give more total protein than other European countries particularly in infancy. Supplements of essential amino acids (EAA) were prescribed for 38% [n=174] of the patients overall, but were given more commonly in arginase deficiency (74%), CPS (48%) and citrullinaemia (46%). Patients in Germany (64%), Portugal (67%) and Sweden (100%) were the most frequent users of EAA. Only 18% [n=84] of patients were prescribed tube feeds, most commonly for CPS (41%); and 21% [n=97] were prescribed oral energy supplements. ConclusionsDietary treatment for UCD varies significantly between different conditions, and between and within European IMD centres. Further studies examining the outcome of treatment compared with the type of dietary therapy and nutritional support received are required.

Dietary management of urea cycle disorders: UK practice

There is no published data describing UK dietary management of urea cycle disorders (UCD). The present study describes dietary practices in UK inherited metabolic disorder (IMD) centres. Cross-sectional data from 16 IMD centres were collected by a questionnaire describing the management of UCD patients on prescribed protein-restricted diets. One hundred and seventy-five patients [N-acetylglutamate synthase deficiency, n = 3; carbamoyl phosphate synthase deficiency (CPS), n = 8; ornithine transcarbamoylase deficiency (OTC), n = 75; citrullinaemia, n = 41; argininosuccinic aciduria (ASA), n = 36; arginase deficiency, n = 12] were reported; 70% (n = 123) aged 0-16 years; 30% (n = 52) >16 years. Prescribed median protein intake decreased with age (0-6 months: 2 g kg(-1) day(-1); 7-12 months: 1.6 g kg(-1) day(-1); 1-10 years: 1.3 g kg(-1) day(-1); 11-16 years: 0.9 g kg(-1) day(-1) and >16 years: 0.8 g kg(-1) day(-1)) with little variation between disorders. Adult protein prescription ranged 0.4-1.2 g kg(-1) day(-1) (40-60 g day(-1)). In the previous 2 years, 30% (n = 53) were given essential amino acid supplements (EAAs) (CPS, n = 2; OTC, n = 20; citrullinaemia, n = 15; ASA, n = 7; arginase deficiency, n = 9). EAAs were prescribed for low plasma quantitative essential amino acids (n = 13 centres); inadequate natural protein intake (n = 11) and poor metabolic control (n = 9). From diagnosis, one centre prescribed EAAs for all patients and one centre for severe defects only. Only 3% (n = 6) were given branch chain amino acid supplements. Enteral feeding tubes were used by 25% (n = 44) for feeds and 3% (n = 6) for medications. Oral energy supplements were prescribed in 17% (n = 30) of cases. In the UK, protein restriction based on World Health Organization 'safe intakes of protein', is the principle dietary treatment for UCD. EAA supplements are prescribed mainly on clinical need. Multicentre collaborative research is required to define optimal dietary treatments.

Suggested guidelines for the diagnosis and management of urea cycle disorders.

Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification/arginine synthesis due to defects affecting the catalysts of the Krebs-Henseleit cycle (five core enzymes, one activating enzyme and one mitochondrial ornithine/citrulline antiporter) with an estimated incidence of 1:8.000. Patients present with hyperammonemia either shortly after birth (~50%) or, later at any age, leading to death or to severe neurological handicap in many survivors. Despite the existence of effective therapy with alternative pathway therapy and liver transplantation, outcomes remain poor. This may be related to underrecognition and delayed diagnosis due to the nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity. These guidelines aim at providing a trans-European consensus to: guide practitioners, set standards of care and help awareness campaigns. To achieve these goals, the guidelines were developed using a Delphi methodology, by having professionals on UCDs across seven European countries to gather all the existing evidence, score it according to the SIGN evidence level system and draw a series of statements supported by an associated level of evidence. The guidelines were revised by external specialist consultants, unrelated authorities in the field of UCDs and practicing pediatricians in training. Although the evidence degree did hardly ever exceed level C (evidence from non-analytical studies like case reports and series), it was sufficient to guide practice on both acute and chronic presentations, address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Also, it identified knowledge voids that must be filled by future research. We believe these guidelines will help to: harmonise practice, set common standards and spread good practices with a positive impact on the outcomes of UCD patients.

Arginine extravasation leading to skin necrosis

Arginine hydrochloride is used in the evaluation of short stature and in the management of urea cycle disorders. In recent times, it has been used in the treatment of stroke-like episodes of MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes). We want to highlight the need for good intravenous access and monitoring the drip site to prevent extravasation injuries that can be caused by arginine, which is a hyperosmolar solution.

Brain glutamine by MRS in a patient with urea cycle disorder and coma

In patients who undergo metabolic decompensation from urea cycle disorders, cerebrospinal fluid glutamine level may be a better marker of cerebral dysfunction than blood ammonia or glutamine levels. However, obtaining cerebrospinal fluid by lumbar puncture carries risk in these acutely ill patients with cerebral edema. Using magnetic resonance single voxel spectroscopy as an alternative to cerebrospinal fluid analysis, elevated brain glutamine/glutamate complex levels were detected in a patient with carbamyl phosphate synthetase deficiency, who had been comatose for many days after normalization of blood ammonia and improvement in blood glutamine levels. Brain glutamine by single voxel spectroscopy decreased toward normal with neurologic recovery. We conclude that brain glutamine may be a better marker than serum ammonia for the management of urea cycle disorders, particularly in patients with prolonged mental status changes.

Problems in the management of urea cycle disorders

Several recent reviews describe the management of urea cycle disorders. There is much agreement on diet, alternative pathway therapy, maintenance of arginine and ornithine levels in acute and chronic management, sick-day regimens, and some aspects of monitoring. However, differences remain in several areas, and physicians at most treatment centers have relatively little experience, because these disorders are rare. Early suspicion of the diagnosis of a urea cycle disorder, and prompt referral to a tertiary center is vital. Drug treatment using chronic administration of sodium benzoate has been abandoned by some centers, but the acceptability of phenylbutyrate is an issue for many patients. Using citrulline chronically is not always successful in recommended doses, and may result in an arginine level too low for maximum control. Appetite and nutrition problems are common. One major concern is the early identification and management of chronic catabolism, theoretically easy, but hard in practice. Biochemical measurement problems complicate monitoring, and there are disagreements about the optimum way of identifying OTC carriers. It is not always clear whom to treat. Within a kindred with an early-onset phenotype, an asymptomatic newborn girl may need treatment for some undetermined time, but target values for monitoring are not clear. In late-onset phenotypes, management of asymptomatic males identified by family screening is also difficult. Most centers do not have sufficient cases to solve these conundrums, some of which require further multicenter study. This paper examines the recommendations of a consensus conference on management, outlines some remaining problems, and incorporates in the text the points raised in open discussion during a session of a symposium held in Sydney in 2003 entitled “New Developments in Urea Cycle Disorders.”

The nutritional management of urea cycle disorders

Diet is one of the mainstays of the treatment of patients with urea cycle disorders. The protein intake should be adjusted to take account of the inborn error and its severity and the patient’s age, growth rate, and individual preferences. Currently, the widely used standards for protein intake are probably more generous than necessary, particularly for those with the more severe variants. Most patients, except those with arginase deficiency, will need supplements of arginine, but the value of other supplements including citrate and carnitine is unclear. Any patient on a low-protein diet should be monitored clinically and with appropriate laboratory tests. All should have an emergency (crisis) regimen to prevent decompensation during periods of metabolic stress. (J Pediatr 2001;138:S40-S45)

UREA CYCLE DISORDERS

Deficiency of any of the five enzymes in the urea cycle results in the accumulation of ammonia and leads to encephalopathy. Episodes of encephalopathy and associated symptoms are unpredictable and, if untreated, are lethal or produce devastating neurologic sequelae in long-term survivors. Although these disorders do not produce liver disease, the consequences of hyperammonemia resemble those seen in patients with hepatic failure or in a transient interference with the urea cycle, as seen in some forms of organic acidemias. Therefore, investigation for hyperammonemia in any infant or child with altered mental status (in the absence of obvious causes, such as trauma, infection, or poisoning) is essential for prompt diagnosis of urea cycle disorders and institution of treatment to avoid brain damage and death. This article addresses the function of the urea cycle and the diagnosis and management of urea cycle disorders.

Evaluation and management of urea cycle disorders using stable isotope infusions

Diagnosing partial urea cycle deficiencies based on clinical and laboratory data is difficult and there is often poor correlation between genotype, in vitro enzyme activity, and phenorypic expression. We have used stable isotope infusions to measure total body glutamine and urea flux for the evaluation of patients with urea cycle disorders. We have previously determined the rate of total body urea production by measuring blood 13C-urea isotopic enrichment during an infusion with the stable isotope 13C-urea, and the proportional contribution of peripheral nitrogen to urea synthesis by measuring the incorporation of 15N from 15N glutamine into 15N urea. The ratio of the isotopic enrichments of 15N urea/15N-glutamine (15N-U/G) allowed us to distinguish carriers for omithine transcarbamylase deficiency (OTCD) both from their affected offspring and from normal control subjects (Lee et. al., submitted). Collectively these data suggest that the flux from 15N glutamine to 15N urea is a sensitive measure of urea cycle activity and is capable of differentiating female carriers for OTCD from normal controls.We have now applied this method to the 1) diagnosis of asymptomatic at risk partial OTCD females, 2) titration of dietary protein tolerance for managing a severe OTCD male patient, and 3) comparison of differences in the bioavailability of enteral vs. systemic sources of nitrogen for total body urea production. By determining the 15N-U/G ratio in 5 at-risk females in two OTCD sibships in whjch mutations were not found in the index case, we were able to measure normal and abnormal urea production and determine carrier status. In the second case, we determined total body glutamine flux at 1.2 gm/kg/day and at 0.8 gm/kg/day protein intake in a 7 month null activity OTCD male to titrate protein tolerance and guide dietary therapy. In the third case, we tested the hypothesis that intestinally generated ammonia and alanine are more effective immediate precursors for urea synthesis than peripherally generated glutamine and as a consequence individuals who have a compromised urea cycle activity would metabolize excessive dietary protein more effectively than peripherally generated protein. By comparing the transfer of 15N from oral and intravenous 15NH4Cl to urea, we found that individuals who have partial urea cycle activity metabolize excessive dietary protein more efficiently, underlying the observation thai these patients are particularly susceptible to stress and fasting. In conclusion this approach may also lead to improvements in the nutritional management of patients with urea cycle defects and those who are severely catabolic during critical illness.